CZ227799A3 - Derivative of nitromethyl thiobenzene functioning as aldoreductase inhibitor, process of its preparation and pharmaceutical composition containing thereof - Google Patents

Abstract

The invention concerns novel compounds of general formula (1) in which: P, T1, T2, X and n are as defined in claim 1, their tautomeric forms, and their additive salts with pharmaceutically acceptable bases. The invention also concerns methods for preparing these compounds and their applications as medicines. These compounds inhibit the aldose reductase enzyme and can be used in the treatment or prevention of peripheral and autonomous neurological diabetic complications, renal and ocular disorders such as cataract and retinopathy.

Description

,Field of technology

The invention relates to a nitromethylthiobenzene derivative as an aldose reductase inhibitor, a method of its preparation and a pharmaceutical composition containing it.

Current state of the art (Oxamido- and ureidophenysu 1 fony 1 ) nitromethanes are described in European patent file number 469SS9.

The essence of the invention

The essence of the invention is a derivative of nitromethylthiobenzene of general formula I

P-NH

(i) where means group i) -(CO-NH)m-SOj-R, group i i)

-C0-(A-C0)u-NH-U /

z »···· Β « · or group i i i )

S(O)nC~N ¹ o' X where means

R is a phenyl group. benzyl, diphenylmethyl, naphthyl, cycloalkylalkyl with 1 to 4 carbon atoms in the alkyl part and with 3 to 7 carbon atoms in the cycloalkyl part and a styryl group, whereby these groups are optionally substituted by one or more Z groups, which are the same or different, or means aromatic a heterocyclic group with 3 to 5 carbon atoms with one or two heteroatoms from the group consisting of an oxygen, sulfur and nitrogen atom, optionally substituted by one or more Z groups which are the same or different and optionally conjugated to one or two phenyl rings , which are optionally substituted by one or more Z groups, which are the same or different, or means an alkyl group with 1 to 4 carbon atoms, optionally substituted by one or more halogen atoms, which can be a cycloalkyl group with 3 to a cycloalkylalkyl group with a cycloalkylalkyl group and with 1 to 10 carbon atoms, a halogen atom, an alkyl group with up to 4 carbon atoms, an 1- to 4-carbon alkoxy group, a nitro group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group, and a 1-alkylamino group with 2 to 5 carbon atoms, and a 1-alkylsulfonyl group with 1 up to 4 carbon atoms, and 1 chi11 group with 1 to 4 carbon atoms and a phenyl group, a hydrogen or halogen atom, the same or different, 7 carbon atoms or up to 7 carbon atoms carbon atoms in al« · « · · * · · · · * «»····«« *· ·* m O or 1, η 0, 1 or 2,

Ti and T2 are independently a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, where O or 1

And an alkylene group with 1 to 8 carbon atoms or a group of the general formula

LytCHJwhere y represents an integer of 0, 1, 2, 3 and 4, while if P represents a group ii), A may also represent the bond of its tautomeric form and an addition salt with a pharmaceutically acceptable base i.

The term alkyl with 1 to 4 carbon atoms means a linear or branched saturated hydrocarbon group containing 1 to 4 carbon atoms. above meaning.

An aromatic heterocyclic group having 3 to 5 carbon atoms contains 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; preferred such groups are furan, thiophene, pyrrole, oxazole, thiazole, imidazo, pyrazole, isoxazole, isothiazo, pyridine, pyridazine, pyrimidine and pyrazine, pyridine and thiophene groups.

The term halogen means an atom of fluorine, bromine, chlorine or iodine.

Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. According to the invention, cycloalkyl and alkyl group means an alkyl group substituted by a cycloalkyl group.

By "alkylene" is meant a linear or branched divalent hydrocarbon group with a saturated chain, such as -CH2-, "CH2-CH2-CH2-, or -CH2-CH(CH3)-CH2-.

The general formula group corresponds to the following general formula groups

-(CHJy-C H(CH ₂ )y-

where y is 0, 1, 2, 3 or 4

In the case where P means group ii) of the general formula í ° οι

X

-CO-{A-CO)u-NH- /—S{O)n-C-N i °

T;

means an A bond, an alkylene group with 1 to 8 carbon atoms and a group of the general formula

ŤHCHWhere y is an integer O, 1, 2, 3 and 4.

··« · ·· · «

In the case where, on the other hand, P represents the group -(CO-NH)m-SO2-R or group iii) of the general formula

X by *

X, ~ o

means A alkylene group with 1 to S carbon atoms and a group of the general formula

where y is an integer of 0, 1, 2, 3 and 4.

Possible tautomeric forms of compounds of general formula I are an integral part of the invention.

Addition salts with pharmaceutically acceptable bases of compounds of general formula I, where X is a hydrogen atom or 2, also form an integral part of the invention. Examples include salts with alkali metals or with metals of alkali metals, such as sodium, potassium, calcium or magnesium salts, an aluminum salt, an ammonium salt or a salt of an organic base having a pharmaceutically acceptable cation.

As the first group of preferred compounds, the compounds of general formula I are mentioned, where P means the group -(CO-NH)m-SO2-R,

R a phenyl, diphenylmethyl, naphthyl and styryl group, where these groups are optionally substituted by one or more Z groups, which are the same or different, or • · · · · · 0 «|*« ···· ·« ·« ·· ··

R represents an aromatic heterocyclic group with 3 to 5 carbon atoms with one or two heteroatoms from the group consisting of an oxygen, sulfur and nitrogen atom, optionally substituted by one or more Z groups, which are the same or different and optionally conjugated with one or two phenyl rings which are optionally substituted by one or more Z groups which are the same or different, or

R stands for an alkyl group with 1 to 4 carbon atoms, optionally substituted by one or more halogen atoms, which may be the same or different, a alkyl group with 3 to 7 carbon atoms or a cycloalkyl group and an alkyl group with 3 to 7 carbon atoms in the cycloalkyl portion and with 1 up to 4 carbon atoms in the alkyl part,

Z, X, m and n have the meaning given in general formula I.

As the second group of preferred compounds, the compounds of general formula I, where P means the group -(CO-NH)m-SO2-R, where it means

R is a phenyl group; a phenyl group substituted with one or more Z groups which are the same or different; a benzyl group; a benzyl group substituted by one or more Z groups which are the same or different; an alkyl group with 1 to 4 carbon atoms, optionally substituted by one or more halogen atoms, which are the same or different; cycloalkyl group with 3 to 7 carbon atoms: cycloalkyl and 1alkyl group with 3 to 7 carbon atoms in the cycloalkyl part and with 1 to 4 carbon atoms in the alkyl part; styryl group; thienyl; pyridyl; naphthyl; dibenzofuryl; or diphenylmethyl;

Z is a halogen atom, an alkyl group of 1 to 4 carbon atoms, an alkoxy group of 1 to 4 carbon atoms, a nitro group, a trifluoromethyl group, a trifluoromethoxy group, and a 1-alkylamino group of 2-5 carbon atoms, and a 1-alkylsulfonyl group of 1-4 carbon atoms and a phenyl group, • · · · ·»' and X, man have the meaning given in general formula I.

Of this second group of preferred compounds, particularly preferred are compounds where P means the group -{CO-NH)m-SOa-R, where means

R is a phenyl group; a phenyl group substituted with one or more Z groups which are the same or different; a benzyl group; a benzyl group substituted by one or more Z groups which are the same or different; a methyl group; a cycloalkyl group having 3 to 7 carbon atoms; cycloalkyl and alkyl with 3 to 7 carbon atoms in the cycloalkyl moiety and with 1 to 4 carbon atoms in the alkyl moiety; styryl group; thienyl; pyridyl; naphthyl; dibenzofurs by hunting; diphenylmethyl or 2,2,2-trifluoroethyl;

From fluorine, chlorine, bromine, methyl group, methoxy group, nitro group, trifluoromethyl group, trifluoromethoxy group, acetamido group, methylsulfonyl group and phenyl group,

X is a hydrogen or chlorine atom, man has the meaning given in the general formula I.

As a third group of suitable compounds, the compounds of the general formula I, where P means the group -(CO-NH)m-SO2-R, where it means

R is a phenyl group; a substituted phenyl group with one or more Z groups which are the same or different; a methyl group; a cycloalkyl group with 3 to 7 carbon atoms or a cycloalkyl group with 3 to 7 carbon atoms in the cycloalkyl moiety and with 1 to 4 carbon atoms in the alkyl moiety; styryl group; thienyl; pyridyl; naphthyl; dibenzofuryl; diphenylmethyl or 2,2,2-trifluoroethyl,

From fluorine, chlorine, bromine, methyl group, methoxy group, nitro group, trifluoromethyl group, trifluoro9« · • 99 ··· 9 99 · 9 methoxy group, acetamido group. a methylsulfonyl group and a phenyl group.

X is a hydrogen or chlorine atom, man has the meaning given in the general formula I.

As a fourth group of suitable compounds, the compounds of general formula I are mentioned, where

S(O)n-C-N I ’ where means

A bond or an alkylene group with 1 u, η, X, Ti and Ti have the meaning given up to 8 carbon atoms, in the general formula I.

As a fifth group of suitable compounds of the general formula I, where P means a group of the general formula, are listed with 1 ou-

S{O)n

where means

And a group of general formula

ÍJ-ÍCHjy.

η, X, y, Ti and T2 have the meaning given in general formula I.

The following compounds are particularly preferred: N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]benzenesulfone• · ·« • * * * · · · · • · · » · · · * · * · «· ♦ ♦ · · · • ·····« ·«· «·· • · · · · · 4 ·

4··· ··*♦ ·· ·· ·· ·· amide,

3.4-difluoro-N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-benzenesulfonamide,

3-bromo-N-[3,5-dimethyl-4-[(nitromethy 1 ) su 1 phony 1 ] pheny 1 ]benzenesulfonamide,

N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2-(trifluoromethyl)benzenesulfonamide,

Ϊ N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl Jphenyl]-4-fluorobenzenesulfonamide,

N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-3-fluorobenzenes u1f onam i d,

N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl-1-phenyl-phenylmethanesulfonamide,

2,3-difluoro-N-[3,5-dimethyl-4-[(nitrimethyl)sulfonyl]phenyl]benzenesulfonamide,

3.5-difluoro-N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]benzenesulfonamide,

N-[3,5-dimethyl-4-[(nitromethyl)su-1-phenyl]-2-fluorobenzenesulfonamide, and the following compounds:

N,N'-bis[3,5-dimethyl-4-[(nitromethyl)sulfonyljphenyl]-1,5-pentenediamide,

N,N'-bis[4-[(nitromethyl)sulfonylphenyl]-1,8-octanediamide, N,N'-bis[4-[(nitromethyl)sulfonylphenyl]-1,5-pentanediamide, N,N'- bis[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]ethand amide,

N,N'-bis[3,5-dimethyl-4-[(nitromethyl)sulphone 1]phenyl]urea na, N,N'-bis[3,5-dimethyl-4-[(nitromethyl )sulfonyl-phenyl]-1,4-butanediamide,

N,N'-bis[3,5-dimethyl-4-[(nitromythy1)sulfonyl-phenyl]-1,3-propanediamide,

N,N'-bis[3,5-dimethyl-4-[(nitromethyl}sulfonyl]-1,3-benzenesulfonamide,

N,N'-bis[3,5-dimethyl-4-[(nitromthy1,sulfonyl]phenyl]-1,3-benzenedimethanesulfonamide).

♦ 9 · · * · · · · · · 999 ··· • 9 <«·· ♦ · • 999 «999 99 99 99 99

99 9

The compounds according to the invention are prepared in the following ways:

AND)

If P represents the group -(CO-NH)m-SO2-R, X is a hydrogen atom, m O and n 2, the sulfonyl chloride of the general formula RSO2CI, where R has the above meaning, is allowed to react with the compound of the general formula II

so ₂ -ch ₂ -no ₂ (II) where T 1 and T 2 have the meaning given in the general formula I, in the presence of a suitable base.

The reaction is preferably carried out in a solvent, for example in a polar aprotic solvent such as tetrahydrofuran, at a temperature of 10°C to the boiling point of the solvent used.

Calcium carbonate (method A1) or pyridine (method A2) are particularly suitable bases.

b)

If P represents the group -(CO-NH) _m -SO2-R, X is a halogen atom, preferably chlorine, m 0 and 2, a suitable N-halogensuccinimid is allowed to react with the compound of general formula III

R - SO ₂

(III) where R, T 1 and T 2 are as defined in formula I, in the presence of a free radical generator such as 2,2'-azobisisobutyrone i t r i 1 .

The reaction is preferably carried out in a solvent, for example • ·

1 • · * 0 0 0 000 0 0 0 0 0 0004 0 ·

0000 0000 00 00 0* 00 in a hydrocarbon solvent such as tetrach 1 ormethane while maintaining the boiling temperature.

C)

If P means the group -(CO-NH) _m -SO2-R, X is a hydrogen atom, m 1 and 2, sulfonyl isocyanate of the general formula R-SO2-N=C=O, where R has the above meaning, is allowed to react, a compound of general formula II, defined above.

The reaction is preferably carried out in a solvent, for example a hydrocarbon solvent such as methyl chloride. at room temperature.

d)

If P represents the group -(CO-NH)m-SO2-R, X is a hydrogen atom, m and n 0, sulfonyl chloride of the general formula RSO2CI, where R has the above meaning, is allowed to react with the compound of the general formula X

wherein T 1 and T 2 have the meaning given for general formula I, in the presence of a suitable base.

The reaction is preferably carried out in a solvent, for example a polar aprotic solvent such as tetrahydrofuran at room temperature. A particularly preferred base is calcium carbonate.

E)

If P represents the group -(CO-NH)m-SO2-R, X is a hydrogen atom, m O and η 1, an oxidizing agent such as m-chloro- 12 · · 4 4 · · 4 · · 4 • 4 4 is allowed to react * 4 · 4 9 4 4 · • · * 4 · 4 4» 9*4 ··· « 4 · · 4 4 4 4 «•94444« «4 44 ·· «4 peroxybenzoic acid with the compound of general formula IV

- CHj - NO, (V) where R, T 1 and T 2 are as defined above.

The reaction is preferably carried out in a solvent such as chloroform at room temperature.

If P stands for group ii) of the formula

Z ^T '

-CO-{A'CO)tJ-NH-C >—S(O)n-C-N* x

u 1, X is a hydrogen atom and n 2, the dichloride of general formula V is allowed to react

Cl-(CO-A)u-COC1 (V) with at least two mole equivalents of a compound of general formula II, defined above, in the presence of a base.

The reaction is preferably carried out in a solvent, for example in a polar aprotic solvent such as tetrahydrofuran, at a temperature of 10°C to the boiling point of the solvent. As bases, calcium carbonate (method F1) or pyridine (method F2) are particularly suitable.

The molar ratio of the compound of general formula II to the compound of general formula V is preferably 2 to 4. A larger amount of aniline derivative can be used without adverse effects.

· ·

99 · 9 9 · 9 · • 9 9 9 9 9

9 9 9 9 9· ··

G)

If P stands for group iii) of formula x O

X is a hydrogen atom and n 2, sulfonyl dichloride of general formula VI is allowed to react

CI-SO2-A-SO2-Cl (VI) with at least two molar equivalents of the compound of general formula II, defined above, in the presence of a base.

Also in this case, examples of suitable bases are calcium carbonate (method G1) or pyridine (method G2).

The reaction is preferably carried out in a polar solvent, at a temperature of 10°C to the boiling point of the solvent.

In general, it is sufficient to react 2 to 4 molar equivalents of the compound of the general formula II with the dichloride of the general formula VI, however a larger amount does not disturb the reaction.

H)

If P means group ii) formula x o ;

-CO-(A-CO)u-NH S(O)nCN * OX ^u

where u is zero, X is a hydrogen atom and n 2, trichloromethyl chloroformate is allowed to react with at least two molar equivalents of the compound of general formula II, defined above, in the presence of a base.

4·

4 4* · 4*4

The reaction is preferably carried out in a polar aprotic solvent such as tetrahydrofuran at a temperature of 10°C to the boiling point of the solvent.

Calcium carbonate is particularly suitable as a base. The molar ratio of the compound of general formula II to trich1-methyl-1-ch1-orformate is preferably 2 to 4.

The intermediate product of the compound of general formula II, defined above, is obtained by the method according to the world patent document number WO 90/08761 by alkaline hydrolysis of the compound of general formula IX. The compound of general formula IX is prepared in the following manner, in particular using a novel reaction of sodium nitromethane with ary-1thiocyanate of general formula VII to give the compound of general formula VIII:

HjN

DMF 10 -20*

CuSO ₄ /NH ₄ SCN

SCN. ch ₃ things

NEt ₃ / CH ₂ CI ₂

CHj - CO - NH·^ SCN \

That is vi r ch ₃ no ₂

KMnOj

AcOHIH ₂ O

CHNONA/DMF

IX

CHj-NO,

The intermediate product of general formula X is obtained by basic hydrolysis of the compound of general formula VIII

VII I

X

9« 9« M I' ·· ·· • 9 · * 4 4 4 «9** • 4 4 4444 4 44 4 φ 4 «4 44 44 4*4 4 4«

444* 4 4

4944 44 44 44 44 4* 44

A specific embodiment of the method is based on the preparation of 3,5-dimethyl-4-[(nitromethyl)sulfone 1]ni 1 i nu, which corresponds to the compound of general formula II, where Ti and T2 mean the group -CH3

Inhibition of the enzyme and 1dosreductase and reduction of sorbitol accumulation can be demonstrated by standard laboratory tests.

1) In vitro studies: inhibition of 1dos reductase

The alpha reductase used is obtained in the lens of male Wistar rats by a modified method described by Hayman et al. (Journal of Biological Chemistry 240, p. 877, 1965). The enzyme extract is diluted with phosphate buffer in the presence of NADPH and with different concentrations of the tested products. The reaction is controlled by L-glyceraldehyde and the progress of the reaction is measured by monitoring the disappearance of NADPH by spectrophorometry at 340 nm. The reaction rate is calculated for some concentration of the test products and the concentration required for a 50% reduction in the reaction rate (IC50) is estimated by linear interpolation.

2) In vivo study: reduction of sorbitol accumulation

Male Wistar rats weighing 200 to 250 are injected intravenously with streptozotocin (60 mg/kg), rendering them diabetic. They are then given orally the test compounds in the form of a suspension 4 hours, 30 hours and 52 hours after the streptozotocin injection. Eighteen hours after the final oral treatment, rats are killed, decapitated, and sciatic nerves removed. After extraction, the level of sorbitol in the nerves is measured by the enzymatic method described by H.J. Bergmeyer (Methods of enzymatic analysis, ed. H.U. Bergmeyer, Academie Press New York 3, p. 1323, 1974). The percentage of protection for each product relative to the group of diabetic animals is calculated, taking into account the level of sorbitol in the sciatic nerves of non-diabetic rats.

« * ♦ *

• 9

9999 9999 ·* ·· ·· • · · « · * » « · ··· · · · · * * · 9 9 9 99 999 • 9 9 9 * · ·· «« · » ·

The following table shows the results obtained for some examples of products.

Product according to example number í 10

34

Aldose reductase inhibition in vitro

IC 50 (mM)

7 6

9

Protection against increased sorbitol (%) mg/kg/day p.o.

70 70 80 85

104 7 1

The compounds according to the invention are used as medicinal products as inhibitors of 1-dos reductase and especially for the treatment of diabetic complications such as cataracts, retinopathy, neuropathy, nephropathy and such as certain vascular diseases.

These drug products can be administered orally in the form of immediate-release or controlled-release tablets, gelatin capsules or granules, intravenously in the form of injectable solutions, transdermally in the form of adhesive transdermal preparations, or topically in the form of eye drops, solutions, creams or gels.

the active substance is combined with various pharmaceutical excipients. The daily dose is 5 to 200 mg of the active substance.

By way of example, without the intention of any limitation, the following pharmaceutical compositions are mentioned:

ft. ft

Composition for immediate release tablet active substance excipients: lactose, wheat starch, polyvidone. talc, magnesium stearate

Composition for controlled release tablet active substance excipients: lactose, polyvidone, talc, magnesium stearate, polymer (cellulose derivative or acrylic or methacrylic derivative or vinyl or glyceride derivative)

Composition for gelatin capsule active substance excipients: lactose, wheat starch, talc, magnesium stearate

Composition for the vial of injectable solution active substance excipients: mannitol, water for injections,

Composition for the cream (composition for 100 g of cream) active substance excipients: spontaneously emulsifying cetyl stearyl alcohol, 1 aryl octanoate, nipasol, sorbic caseline, propylene glycol, carbopol,

Composition for eye drops, active ingredient, excipients: sodium chloride, benzonium chloride, water for injections.

100 mg

100 mg

100 mg

200 mg mg

The following examples of practical implementation clarify the invention in more detail, but do not limit it in any way.

In the case of nuclear magnetic resonance (NMR), the abbreviation is used, where s means singlet, d doublet, t triplet, q • ti ti quartet, m complex multiplet; the chemical shift δ is expressed in ppm.

Example 1 (Method A1)

N-[3,5-Dimethyl hyl-4-[(nitrimethyl hy1 )sulfone 1]phenyl]benzenesulfone; and m i d

7.85 g (7S.4 mmol) of calcium carbonate and 7.45 g (58.4 mmol) of benzene chloride are added successively to a mixture maintained under nitrogen and containing 9.5 g (38.9 mmol) of 3,5-dimethyl-4- [(nitromethyl)sulfones] I and nu in 180 ml of tetrahydrofuran. The reaction medium is refluxed for eight hours. After the addition of 2.5 ml (19.6 mmol) of benzenephonone chloride, boiling under a reflux condenser is continued for another six hours. An additional 2.5 ml (19.6 mmol) of benzene 1 fone 1 ch 1 oride is added and reflux is continued for 22 hours. After cooling, the reaction mixture is poured into 600 ml of water and extracted with methylene chloride. The combined organic extracts were dried over sodium sulfate and evaporated to dryness under reduced pressure. The paste-like residue obtained is purified by chromatography on a silica column (using methylene chloride as an eluent) and recrystallization from a mixture of hexane and methylene chloride. yielding 6.2 g (41% theory) of N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]benzenesulfonamide. Melting point is 129 to 131 °C (hexane/methylene chloride).

Elemental ana 1 yza CisHieNjOeSj (M = 384.41) calculated found

C%

46^86

47 _} 16

IR: V= 3241, 1594, 1558 1090, 601 cm' ^{1 X} H NMR (DMSO-d ₆ ) : interchangeable with

4 _? 20

4.14

1474, 1349,

N% .29 7 _f 38 1322,

WITH%

16.68 16 .87

1160, 1140, (2H, δ = 2.52 (6H, s) );

CF3COOD); 7 _; 04 (2H, s); 7.63-7.72 (3H, m); 7^94-7.97 (2H, m); 11 _? 16 (1H, s, interchangeable with CF ₃ COOD) .

with, • 9 9 ««99 · «9 9 * * 99 99 99 9 9 9 999

9999*999 9 · 99 99 99

The starting 3,5-dimethyl1-4-[(nitromethyl)su1phones 1]ani 1 and π are prepared by performing steps 1 through 5 sequentially:

Grade 1

251.2 g (3.30 mol) of ammonium thiocyanate is rapidly added to a solution maintained under nitrogen and containing 121 g (1 mol) of 3,5-cl i me th y 1 an i 1 i nu in 1.75 1 of anhydrous N, of N-dimethylformamide. The temperature will rise from 18 to 35 °C. After one and a half hours, the temperature of the solution is returned to room temperature and 263.3 g (1.65 mol) of anhydrous sodium sulfate is quickly added. The reaction medium is stirred at room temperature for three days and poured into S liters of water. The pH value is adjusted to 7.5 by adding 550 g (6.55 mol) of sodium bicarbonate. The reaction medium was filtered, the solid was washed with ethyl acetate, and the liquid was extracted with ethyl acetate. The combined organic liquid phases are washed with 500 ml of water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The obtained pasty residue is recrystallized from 500 ml of hexane, thereby obtaining 128.8 g (72% of theory) of 4-amino-2,6-dimethylphenylthiocyanate, which is used in the next step without purification.

IR: v = 3483, 3382, 2142, 1627, 1591, 1470, 1435, 1342,

1191, 856, 850 cm' ¹

NMR (DMSO d ₅ ): δ - 2 _; 58 (6H, s); 5.86 (2H, s); 6 _y 65 (2H, s, interchangeable with CF;. COOD)

Level 2

46.9 g (463 mmol) of triethylamine is rapidly added to a mixture, maintained under nitrogen, containing 75.2 g (422 mmol)

of 4-amino-2,6-dimethylphenylthiocyanate and 500 ml of anhydrous methylene chloride, and 32.8 g (418 mmol) of acetyl chloride are added dropwise. The temperature rises to 41 °C and a precipitate forms. The next day, the reaction mixture is poured into 400 ml of water. The insoluble fraction is isolated by filtration, washed with 100 ml of methylene chloride and dried. 61.8 g (67% of theory) of a tear-beige colored solid with a melting point of 204 to 206 °C are obtained, which essentially consists of 4-acetamido-2,6-dimethylphenylthiocyanate, which in the next stage it is used without cleaning.

IR: v = 1670, 1595, 1541, 1401, 1369, 1325, 1261 cm' ^{1 X} H NMR (DMSO dg ): δ = 2.08 (3H, s); 2.52 (6H, s) , 7 _y 54 (2H, s); 10jl3 (IH, s, interchangeable with CFsCOOD).

^; ,Level 3

9.4 g (174 mmol) of sodium methoxide was rapidly added to a solution, maintained under nitrogen, containing 6.95 mL (128 mmol) of nitromethane in 140 mL of anhydrous N,N-dimethylformamide. The temperature rises spontaneously to 35 °C, the reaction medium is heated to 40 °C and maintained at this temperature for one hour. After cooling to room temperature, 12.9 g (58.6 mmol) of 4-acetamido-2,6-dimethylphenylthiocyanate in 140 ml of anhydrous N,N-dimethylformamide are added dropwise over the course of one hour and 20 minutes. The reaction mixture was stirred for 20 hours at room temperature and the mixture was poured into one liter of water. A solution with a pH value of approximately 10 is obtained, washed twice with 500 ml of ethyl acetate and neutralized to a pH value of 7 with dilute hydrochloric acid. This neutral solution is extracted four times with 500 ml of ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated to dryness under reduced pressure. The obtained solid residue is purified by chromatography on silica (using a 2/1 methylene chloride/ethyl acetate system as an eluent), thereby obtaining 8.3 g (56% of theory) of a solid with a melting point of 160 to 163 C, consisting essentially of N-[3,5-dimethyl-4-[(nitromethyl)thio]phenyl]acetamide.

IR: v = 1666, 1599, 1554, 1554 cm' ^{1 X} H NMR (DMSO d ₆ ): δ = 2 _; 10 (3H, s); 2.46 (6H, s); 5 _? 69 (2H, s); 747 (2H, s); 10j03 (IH, s, interchangeable with CFsCOOD).

* · · *·» a » · * • · » · · Φ · · ····· * · · · · * a a ··*· aaaa ·· ·* «« a*

Level 4

A solution heated to 50°C of 18.6 g (118 mmol) of potassium permanganate in 500 mL of water is added rapidly to a solution of 10.0 g (39.3 mmol) of N-[3,5-dimethyl-4-[ (nitromethyl)thio]phenyl]acetamide in 1 liter of acetic acid. The reaction medium is maintained at 65 ”C for 30 minutes, after which it is cooled to . room temperature in an ice bath. A saturated aqueous solution of metahydrogensulphur or sodium hydroxide is added until the color changes (approximately 25 ml). The reaction mixture is poured into 2.5 L of water and stirred for one hour. The solid formed was filtered off, rinsed with water and dried to give 6.1 g (54% of theory) of a white solid, mp 180-182 C, consisting essentially of N-[3,5-dimethyl1-4 -[(nitromethyl)sulfonyl]pheny 1]acetamide, which is used in the next step without purification.

IR: V = 1677, 1595, 1559, 1534, 1382, 1367, 1330, 1315,

1260, 1152, 871, 746, 639, 615 cm' ¹

NMR (DMSO d _s ): δ = 2.25 <3H, s); 2.71 (6H, s); 6.64 (2H, s, interchangeable with CFsCOOD) '· 7.68 (2H, s); 10.48 (IH, s, interchangeable with CF3COOD)

Level 5

A mixture of 13.1 g (45.8 mmol) of N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]acetamide and 10.6 g (265 mmol) of sodium hydroxide pellets in 150 ml of water is maintained at 80 °C for one hour. After cooling, the reaction mixture is poured into 850 ml of water. The reaction mixture is acidified to pH 5 with acetic acid (approximately 20 mL) to precipitate a solid which is isolated by filtration. The solid was washed twice with 50 mL of water and dried to give 10.6 g (95% of theory) of an elder-colored solid, mp 128-130 °C, consisting essentially of 3,5-dimethyl-1-4-[ (nitromethyl)sulfone 1]ani 1 i nu, which is used in the next step without purification.

The analytical sample is obtained by recrystallization from a mixture of hexane and ethyl acetate.

The melting point is 130 to 132 °C.

Elemental analysis: C ₉ H ₁₂ N ₂ O ₄ S (M = 244.26)

C% H% N% WITH% calculated 44, 25 4.95 11.47 13,13 found 44, 24 4.95 11.55 13,15 í IR: V = 3472, 3374, 1630, 1600, 1550, 1341, 1317, 1154, 72 6 cm' ^{l 1} H NMR (DMSO d _fi ) : δ = 2.40 (6H, s); 6, ,23 (4H, s,

interchangeable with CFaCOOD); 6.35 (2H, s).

Example 2 (Method A2)

N-[3,5-Dimeth hy1-4-[(nitrom t hy1)sulfones 1]pheny1Jbenzenesulfones d

1.08 g (6.11 mmol) of benzenesulfonyl ori du is rapidly added to a mixture maintained under nitrogen containing 1.0 g (4.09 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulfone 1] ani 1 i nu and 0.65 g (8.22 mmol) of pyridine, dried over potassium hydroxide, in 19 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for two hours at room temperature. The next day, the reaction mixture was poured into water and ice and acidified with 1N hydrochloric acid and extracted with methylene chloride. The combined organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The oily residue is purified by silica column chromatography (using methylene chloride as eluent) and recrystallization from a mixture of hexane and methylene chloride to give 1.1 g (70% of theory) of N[3,5-dimethyl-4- [(nitromethyl)sulfonyl]phenyl]benzenesulfonamide exactly the same as the product prepared by the method according to example 1.

Example 3 {Method D)

N-[3,5-Dimethyl-4-[(nitromcthyl)thio]phenylbenzenesulfonamide 0.75 g (7.49 mmol) of calcium carbonate and 1 g (5.66 mmol) of benzenesulfonyl chloride were added to a mixture maintained at nitrogen atmosphere and containing 0.8 g (3.77 mmol) of 3,5-dimethyl 1-4[(nitromethyl)thio]ani 1 i nu in 30 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for three days at room temperature, poured into water and extracted with methylene chloride. The combined organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The obtained residue is purified by column chromatography on silica (using methylene chloride as eluent) to give 0.9 g (68% of theory) of N-[3,5-dimethyl-4-[(nitromethyl)thio]phenyl-3-benzenesulfonamide.

Melting point is 146 to 148°C (hexane/ethyl acetate).

Elementary ana 1 ýz a : C ₁₅ H ₁₆ N ₂ O ₄ S ₂ (Μ = 352 _? 41)

C% H% N% WITH% calculated ⁵¹ 12 4.58 7.95 18,19 to climb 50, 95 4.54 8.03 18.05 IR: v = 3275, 1596, 1554, 1474, 1467 , 1379 , 1323, 1163, 1092, 872, 688 cm' ¹ NMR (DMSO d ₆ ): δ = 2.26 (6H, with) 5.53 (2H, s); 6.85

(2H, s); 7.48-7.60 (1H, s, replace it with (3H, m); 7.74-7.77 with CF ₃ COOD).

<2H, m) ; 10^.46

The starting substance, obtained by the following

3,5-dimethyl-4-[(nitromethyl)thio]an i 1in method:

A mixture of 1.6 g (6.29 mmol) of N-[3,5-dimethyl-4-[(nitromethyl)24 • · thi o ] phenyl]acetamide and 1.44 g (36.0 mmol) of sodium hydroxide pellets in 20 ml of water is kept at a temperature of 80 °C for one hour. After cooling, the reaction medium is poured into water and extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and evaporated to dryness under reduced pressure. The obtained residue is purified by column chromatography on silica (using a 2/1 hexane/ethyl acetate system as eluent) to give 0.8 g (60% of theory) of an oil consisting of 3,5-dimethyl-4-[(nitromethyl )thi o]ani 1 i nu. Ή NMR (DMSO de ): δ = 2.31 (6H, s); 5.43 (2H, s, interchangeable with CFsCOOD); 5.52 (2H, s); 6.39 (2H, s).

Example 4 (Method E)

N-[3,5-Dimethyl-4-[(nitromethyl)sulphyl]phenylbenzenesulfonam

1.3 g (5.46 mmol) of 70-75% m-chloroperoxybenzoic acid is rapidly added to a solution of 2.2 g (6.24 mmol) of N-[3,5-dimethyl 1 -4-[(nitromethyl) of thio]phenyl]benzenesulfonamide in 79 mL of anhydrous chloroform. The reaction medium was stirred for 24 hours at room temperature and poured into a solution of 0.33 g (3.93 mmol) of sodium bicarbonate. The reaction mixture is extracted with methylene chloride. The combined organic extracts were dried over sodium sulfate and evaporated to dryness under reduced pressure. The obtained residue is purified by successive chromatography on a column of silica (using methylene chloride as an eluent for the first chromatography and a 2/1 hexane/ethyl acetate system for the second chromatography) and recrystallization from hexane to obtain 0.98 g (42% of theory ) of N-t3,5-dimethyl-4-[{nitromethyl)sulfinyl]phenyl]benzenesulfonamide.

The melting point is higher than 50 °C (decomposition at a temperature of 130 °C). Elemental analysis: C ₁₅ H ₁₆ N ₂ O ₅ S2 (M = 368.41)

- 25 - • · · · » * 0 0 0 · · 0 0 0 0 000 00 0* 0 · 0 0 0 0 00000000 00 00 0 0 0 0 0 0 0 · 0*0 0*0 0 * 0 0 0 0 C% H% N% with% calculated 48.90 4.38 7.60 17.40 found 48.96 4.66 7.47 17 _{out of} 58 IR: v = 1595, 1557, 1160, 1091, 1074, 602 cm' ^{1 3} H NMR (DMSO d ₆ ): δ = 2.43 and (6H, ,s) ; 6.14 (2H, s, replace the first s CFaCOOD)) 6 .88 (2H, with); 7.57-7.66 {3H, m); 7.85- -7.88 (2H, m) ; 10, .79 (1H, p ' interchangeable with CF3 code)

with CF ³ COOD) .

Example 5 (Method A1)

4-Chloro-N-[3,5-dimethyl-4-[(nitromethyl)sulfone 1]phenylbenzenesulfonate

1.45 g (14.5 mmol) of calcium carbonate and then 2.3 g (10.9 mmol) of 4-chlorobenzenesulfonyl chloride are added successively to a mixture of 1.8 g (7.37 mmol) of 3,5-dimethyl-4-[(nitromethyl )sulfonylaniline in 45 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for 27 hours at room temperature and poured into 200 ml of water. The reaction mixture is extracted three times with methylene chloride. The combined organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica column chromatography (using methylene chloride as eluent) and recrystallization from chloroform to give 0.44 g (14% of theory) of 4chloro-N-[3,5-dimethyl-4-[(nitromethyl) sulfonyl]phenyl]benzene su 1 f onanii du .

The melting point is 160 to 162 °C (chloroform).

Elemental analysis: c ₁₅ H ₁₅ C1N ₂ 0sS2 (M = 418.86)

C% H% N%

43.01 3.61 6.69

42.99 3 _Of 59 6.72 calculated per 1ezeno

I » · · · · « · (2H, s,

6.46 /

IR: v = 1594, 1562, 1346, 1167, 1147, 621 crf ^X H NMR (DMSO d ₆ ): δ = 2.48 (6H, s) exchangeable with CF 3 COOD); 6 _f 99 (2H, (2H, m) ; 7.89-7.93 (2H, m) ; 11.18 (1H, s, interchangeable with CF3COOD)

67-7.72 > i frí k1 ad 6 (Method A2 )

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-3-methylbenzenesulfonamide

1.3 ml (16.1 mmol) of pyridine, dried with potassium hydroxide, and 2.3 g (12.1 mmol) of 3-methylbenzenesulfone 1 in 1 or i du containing 2.0 g of sulfone 1]ani are successively added 1 i nu in a solution maintained under nitrogen and (8.19 mmol) 3,5-dimethyl-4-[(nitromethyl) 50 ml of anhydrous tetrahydrofuran. The reaction medium was stirred for 24 hours, kept at 40°C for one hour and poured into a mixture of 100 ml of water and 100 g of ice. The reaction mixture is acidified to pH 3 by adding 1N hydrochloric acid and extracted three times with 100 ml of methylene chloride. The combined organic extracts were washed with 100 ml of water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica column chromatography (using methylene chloride as eluent) to give 2.3 g (71% theory) of N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl] -3-methylbenzenesulfonamide.

Melting point is 179 to 181 °C (hexane/ethyl acetate).

Elemental analysis: _Ci6 h ₁₈ N ₂ O ₆ S ₂ (M = 398.44) calculated for 1ez eno

C% N% WITH% 48.23 4.55 7.03 16 ^09 48.21 4.61 7.06 15.99

9999 9*99

9> 99

IR: V = 3244, 1594, 1565, 1339, 1308, 1182, 1159, 1148, 607 cm' ^{1 X} H NMR (DMSO d ₆ ): δ = 2.38 (3t, s); 2 _? 48 (6H, s); 6 _; 45 (2H, s, interchangeable with CF3COOD); 6 _; 99 (2H, s); 7^487.53 (2H, m) ; 7.69-7.72 (2H, m); 11.05 (IH, s, interchangeable with CF3COOD).

Example 7 (Method A2)

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-4-methylbenzenesulfonami d

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-4-methylbenzenesulfonamide is obtained by the method of Example 6 using 2.3 g (12.1 mmol) of 4-methylbenzenesulfonyl chloride. Heating maintenance at a temperature of 40 °C takes three hours,

The yield is 0.31 g (10% of theory).

Melting point is 163 to 165°C (hexane/ethyl acetate).

Elemental analysis: _Cl6 H ₁₈ N ₂ O ₆ S ₂ (M = 398.44)

C% H% N% WITH% including eno 48.23 4.55 7.03 _f 09 found / 48 _of 27 4.66 6.97 15 v83 IR: V = 3254, 1596, 1562, 1341, 1309, 1178 , 1161, 1147, 1090, 1071, 664, 635, 599 cm' ¹ h NMR (DMSO d ₆ ): δ = 2.36 (3H, with) 2.47 (6H, s) ; 6.45 (2H, s, replace í te1ny s CF3COOD) ; 6.98 (2H, s) ; 7.41 (2H, d, J = 8 Hz); 7.79 (2H, a, J = 8 Hz); 11.03 (IH,

^s » interchangeable with CF3COOD).

Example 8 (Method A2)

2,4-Difluoro-N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]benzenesulfonamide • · · a · * • · ·*· • · · *· va ·β *·«·· ··»

0.65 g (8.22 mmol) of pyridine, dried with potassium hydroxide, and 1.3 g (6.11 mmol) of 2,4-difluorobenzenesulfone 1 chloride are added successively to a solution cooled to a temperature of approximately 10 °C and containing 1.0 g (4.09 mmol) of 3,5-dimethyl-4[(nitromethyl)sulfonyl]aniline in 20 mL of anhydrous tetrahydrofuran. The reaction medium was stirred for two hours at 10 °C for 20 hours at room temperature and poured into 100 ml of water. The reaction mixture was acidified to pil 3 by adding concentrated hydrochloric acid and extracted with methy 1 enchlor idem. The combined organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The obtained oily residue is purified by silica column chromatography (using methylene chloride as eluent) and recrystallization from toluene to give 0.38 g (22% of theory) of 2,4-difluoro-N-Γ3,5-dimethyl -4-[(nitromethyl)sulfonyl]phenyl]benzenesulfonamide.

The melting point is 154 up to 156 ’C (toluene) • Elemental analysis: (M - 420.40) C% H% F% N% WITH% calculated 42.85 3.36 9.04 6.66 15.25 found 42.81 3.41 8.80 6.69 15,26 IR: V = 3261, 1599, 1559, 1478, 1339, 1165, 1149, 1124, 1075, 866, 672 cm ^{-1 Χ} Η NMR (DMSO d _s ) : δ = 2.48 (6H, with); 6.46 (2H, s, .interchangeable with CFjCOOD) ; 6^98 (2H, s); 7.31-7.37 (IH, m) ; 7.54-7.62 (IH, m) ; 8.09-8, 17 (IH, m); 11.49 {IH, s, interchangeable with CF ₃ C00D) .

Example 9 (Method A2)

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide

N-[3,5-Dimethyl-4-[(nitromthy1)sulfonyl]phenyl] — 3—(tri —

4·

I ·

I · »· · ·· * · » · 444 • 4 · · 4 «·4 • 4· 4

9 fluoromethyl)benzenesulfonamide is obtained by the method of Example 6 using 3.0 g (12.3 mmol) of 3-(trifluoromethyl)benzenesulfonyl chloride. Curing by heating at a temperature of 40 “C takes four hours.

The yield is 1.7 g (46% of theory).

Melting point is 146 to 148°C (hexane/ethyl acetate).

Elemental analysis: C16H15F3N2O6S2 (M = 452.42) C% H% F% N% WITH% calculated 42,47 3.34 12, 60 6.19 14. ,17 found 42.80 / 3.41 12 23 6.26 ¹⁴ : ,50 IR: V = 3244, 1593, 1569, 1359, 1344 , 1326, 1182, 1167,

1148, 1139, 1104, 1071, 641 cm' ¹

NMR (DMSO d ₅ ): δ = 2.48 (6H, s); 6.67 <2H, s, interchangeable with CF3COOD) ; 7.22 (2H, s); 8.09 (ÍH, t,

J = 7.8 Hz); 8 _? 30 (IH, d, J = 8 Hz); 8.38-8.43 (1H, m);

10.44 (ÍH, s, interchangeable with CFsCOOD).

Example 10 (Method A2)

3,4-Difluoro-N-[3,5-dimethyl-4-[(nitrimethyl)sulfonyl]phenyl]benzenesulfonamide

3,4-Difluoro-N-[3,5-dimethyl-4-[(nitromethyl)sulfone 1] pheny 1 ] benzene 1 phonamide is obtained by the method of Example 8 using a solution of 2.0 g ( 8.19 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulfonyl]ani 1 i nu in 40 ml of tetrahydrofuran. 1.3 g (16.4 mmol) of pyridine and 2.6 g (12.2 mmol) of 3,4-difluorobenzenesulfonyl chloride. The reaction medium is stirred successively for one hour at 10°C, for 19 hours at room temperature, for 3 hours at 50°C and for 16 hours at room temperature.

The yield is 1.2 g (35% of theory).

The melting point is 158 to 160 °C (toluene).

• ♦

ft • ft ft · · · · • · · ftft · 4 • · ftftftft ftftftft···· ftft ftft E1emen t ary analysis: CisH ₁₄ F 2 N 2 O ₆ S ₂ (M = 420.40) C% H% F% N% with% calculate eno 42^85 3.36 9; 04 6.66 15.25 for 1 month 42.72 ? 3.33 8. t 83 6 _; 73 15 _{out of} 37 IR: V = 3273, 1600, 1556, 1511, 1362, 1345, 1329, 1277,

1148, 1120, 1069, 637 cm' ^{1 X} H NMR (DMSO d _s ): δ = 2.37 (6H, s); 6.34 (2H, s, ί replaces telny with CF3COOD) ; 6.89 (2H, s); 7.56-7.67 (2H, m); 7.86-7.92 (IH, m); 11.07 (Iris, Ξ, interchangeable ^: with CF3COOD).

Example 11 (Method A2)

N-[3,5-Dimethyl-4-[(nitronethyl)sulfonyl]phenyl]-4-methoxybenzenesulfonami d

1.33 mL (16.4 mmol) of pyridine, dried over potassium hydroxide, and 2.54 g (12.3 mmol) of 4-methoxybenzenesulfone 1CH1OR i du are added successively to a solution maintained under nitrogen and containing 2.0 g (8.19 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulfone 1 Jan i 1 i nu in 40 ml anhydrous tetrahydrofuran. The reaction medium was stirred for 24 hours at room temperature and then at 40 °C for one hour and poured into a mixture of water and ice. The aqueous solution was acidified to pH 1 by addition of 1N hydrochloric acid and extracted with methylene chloride. The combined organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The obtained oily residue is purified by silica column chromatography (using methyl chloride as eluent) and recrystallization from a mixture of hexane and ethyl acetate to give 1.1 g (33% of theory) of N-[3,5-dimethyl-4- [(nitromethyl)sulfonyl Jphenyl]-4-methoxybenzenesulfonamide.

The melting point is 141 to 142 C (toluene).

Elemental analysis: Ci6H _ia N ₂ O7S2 (M = 414.44)

- 31 - 9 ·* 9 9 9 · 9 9 9 9 9 9 9 9·9*99 • 9 9 9 9 9 * 9 9 9 9 · 9*99*9 · C% H% N% with% calculate eno 46,37 4.38 6.76 15.47 found 46.40 4.38 6.89 15,22 IR: v = 3251, 1595, 1557, 1486, 1398, 1346 , 1308, 1260,

1176, 1151, 1148, 1095, 1071, 874, 836, -599 cm ^-1

NMR (DMSO d _s ): δ - 2.58 (6H, s); 3.93 (3H, s); 6.56 (2H, s, interchangeable with CFaCOOD); 7.08 (2H, s); 7 _of 20)7.25 (2H, m) ; 7.92-7.97 (2H, m); 11.07 <1H, s, replace it e1ny with CF3 COOD) .

Example 12 (Method A1)

4-Bromo-N-(3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]benzenesulfonyl

2.0 g (20.0 mmol) of calcium carbonate and 3.5 g (14.9 mmol) of 4-bromobenzenesulfonyl chloride are successively added to a mixture of 2.4 g (9.83 mmol) of 3,5-dimethyl-4 -[{nitromethyl)su]phones 1]ani 1 i nu in 45 ml of anhydrous tetrahydrofuran. The reaction medium was stirred for 20 h at room temperature and then refluxed for 48 h. After cooling, it is poured into 400 ml of water and extracted with methylene chloride. The combined organic extracts were dried over sodium sulfate and evaporated to dryness under reduced pressure. The obtained oily residue is purified by silica column chromatography (using methylene chloride as eluent) to give 1.1 g (24% of theory) of 4-bromo-N-[3,5-dimethyl-4-[(nitromethyl) sulfonyl]phenyl]benzene sulfonamide.

Melting point is 164 to 166°C (hexane/ethyl acetate).

Elemental analysis: CisHisBrN2C>6S2 (M = 463.32) calcd found

C% H% Br% N% 38.88 3.26 17.25 6, 05 39.07 3.38 17.00 5, 93

WITH%

13.84

13.70 • I* · *·<·

IR: V = 3258, 1594, 1568, 1471, 1393, 1342, 1166, 1148,

1088, 1069, 740, 632, 609 cm' ^{1 Χ} Η NMR (DMSO dg ): S = 2.64 (6H, s); 6.62 (2H, s, interchangeable with CFsCOOD); 7.14 (2H, s); 7.99 (4H, s);

11.34 (IH, s, interchangeable with CF3COOD).

Example 13 '{Method A1 )

3-Bromo-N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]benzenesulfonamide

3-Bromo-N-[3,5-dimethyl 1-4-[(nitromethyl)su 1 phenyl]phenyl]benzenesulfonamide is obtained by the method of Example 12 using

3.5 g (14.9 mmol) of 3-bromobenzenesulfonyl chloride. It is oxidized by heating at reflux temperature for 40 hours.

The yield is 0.8 g (1S% of theory).

Melting point is 156 to 153 °C (hexane/ethyl acetate).

Elemental analysis: CisHi5BrN20gS2 (M = = 463.32) C% H% Br% N% calculated 38.88 ³ ? 26 17.25 6.05 found 39.17 3,' 45 17.00 5.,91 IR: V = 3237, 1594, 1565, 1483, 1397 ', 1358, 1340, 1181, 1167, 1148, 1071, 885, 679, 635, 605 cm' ^{1 X} H NMR (DMSO d ₅ ): δ = 2 . 64 (6H, with); 6.62 (2H, s, replace i t e1n in s CT'j COOD) ^{; 7} of 15 (2H, S); 7.70-7.75 (IH, m) ; 8.04-8.07 (2H, m) ; 8, 18-8 ,19 (IH, m) ; 11.33 (IH, s, interchangeable with CF3COOD).

Example 14 (Method A2)

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2-(trifluoromethyl)benzenesulfonamide

N-[3,5-Dimethy1-4-[(nitromethyl)sulfonyl]phenyl]-2-(tri00 0» ·· 00 ·« Bk • * 4 0 0 · • 0 0 «00» «4 Φ

0 0 • 0 · 0 · «000000» 0» 0 fluoromethyl)benzenesulfonamide is obtained by the method according to example 6, starting from a solution of 2.0 g (8.19 mmol) of 3,5-dimethyl-4-[(nitromethyl) sulfones 1]ani 1 i nu in 38 mL of tetrahydrofuran, 1.32 mL (16.3 mmol) of pyridine and 3.0 g (12.3 mmol) of 2-(trifluoromethyl)benzenesulfone chloride. It is cured by heating at a temperature of 40 °C for 8 hours.

The yield is 0.7 g (19% of theory).

Melting point is 171 to 173 °C (hexane/ethyl acetate).

Elemental analysis: c ₁₆ H ₁₅ F ₃ N ₂ O ₆ S ₂ (M = 452.42)

C% H% F% N% WITH% calculated 42 .47 3.34 12.60 6.19 14,17 found 42 .61 3.35 12.32 6.21 14.55 IR: v = 3370, 3028, 2954, 1596, 1562, 1405, 1348, 1340,

1307, 1180, 1166, 1149, 1122 cm' ^{1 Χ} Η NMR (DMSO d ₆ ): δ = 2 _f 42 (6H, s); 6.41 (2H, s,

-interchangeable with CF3COOD) ; 6.93 (2H, s); 7.82-7.91 (2H, m); 7.96-8.01 (1H, m); 8.17-8.20 (1H, m); 11.38 (1H, s, interchangeable with CF3COOD).

Example 15 (Method A2)

N-[3,5-Dimethy 1-4-[(nitromethyl)sulfonyl]-2-naphth. allensulfonami d

1.3 ml (16.1 mmol) of pyridine, dried with potassium hydroxide, and 2.8 g (12.4 mmol) of 2-naphthalenebenzenesulfonyl chloride are successively added to a solution, maintained under nitrogen, containing 2.0 g (8.19 mmol ) 3,5-dimethyl-4-[(nitromethyl)sulfone 1]ni 1 i nu in 40 ml of anhydrous tetrahydrofuran. The reaction medium was stirred for 6 hours at room temperature and then left for two days and poured into 200 ml of water. The aqueous solution was acidified to pH 1 by adding a dilute solution of hydrochloric acid and extracted with methylene chloride. The combined organic extracts are washed twice with water, dried over sulfate ·· »1 ·« «· * * * · * · * » 9 9 · • · 9 · «ÍW » · · « • * · * «· · 9 «· ·*·· • · · « · 4 · ···· «<«| *« »» «« W« sodium and evaporated to dryness under reduced pressure. The solid residue obtained is purified by silica column chromatography (using methyl chloride as eluent) to give 3.0 g (84% of theory) of N-[3,5-dimethyl-4-[(nitromethyl)sulfonylphenyl]-2 -naphthalenesulfonamide.

The melting point is 20°C to 215°C (ethyl acetate), decomposition at a temperature of 215°C.

Elemental analysis: Ci ₉ H ₁₈ N ₂ O _with S ₂ (M = 434 _? 47)

C% H% N% S% calculate eno 52,52 4.18 6.45 14.76 found 52.62 4/29 6.45 14.42 IR: v = 3230, 1557, . 1340, 1180, 1163, 1148, 1072, 659, 641 cm ¹ NMR (DMSO d ₆ ): δ = 2, 54 <6H, s); 6.50 (2H, s, interchangeable with CF ₃ COOD) , ; 7.13 (2H, s); 7.76-7/81 (2H, m); 7.91-7.95 (IH, m) ; 8.10-8.33 (3H, m); 8.77-

8j78 (1H, m); 11/30 (IH, s, interchangeable with CFaCOOD).

Example 16 (Method A2)

N-[3,5-Dimethyl-4-[(nitromthyyl)sulfonyl]phenyl](2-nitrophenyl)methanesulfonamide

N-[3,5-Dimethyl-4-[(nitromethyl)sulfony]phenyl](2-nitrophenyl)methanesulfonamide is obtained by the method of Example 15 using 2.9 g (12.3 mmol) of (2-nitrophenyl) methansu 1fony 1ch1 oř i du. It is stirred at room temperature for 26 hours. The yield is 2.6 g (72% of theory).

Melting point is 189 to 190 “C (hexane/ethyl acetate).

Elemental analysis: _{(M =} 443.44)

C% H% N% WITH% calculated 43.33 3.86 9.48 14/46 found 43.67 3.82 9/60 14/32

*4···444 • 44

4

IR: v = 3243, 1596, 1562, 1531, 1487, 1399, 1361, 1336,

1313, 1160, 1147, 1140, 902, 869, 632 cm' ^{1 X} H NMR (DMSO d ₆ ): δ = 2.58 (6H, s); 5.21 (2H, s); 6.56 (2H, s, interchangeable with CF 3COOD); 6^. 98 (2H, s); 7 _r 61 —

7.64 (1H, m); 7.70-7.80 (2H, m); 8.10-8.13 (1H, m);

10.83 (1H, s, interchangeable with CF3COOD).

and

Example 17 (Method A2)

2-Bromo-N-[3,5-dimethyl]-4-[(nitromethyl)sulfonyl]phenyl]benzenesulfonamide

2-Bromo-N-[3,5-dimethyl-4-1(nitromethyl)sulfonyl]phenyl]benzenesulfonamide is obtained by the method of Example 15 using 2.5 g (9.75 mmol) of 2-brombert from en s u 1 phones 1 ch 1 or i d u . The reaction mixture was stirred for 20 hours at room temperature. An additional 0.6 g (2.35 mmol) of 2-bromobenzenesulfonate is added. Stirring is continued for four hours at room temperature. The yield is 1.6 g (42% of theory).

The melting point is 140 to 142 °C (hexane/ethyl acetate).

Elemental analysis: c^H^BrNsOsS. (M = 463.32)

C% Br% N% calculated found 38.88 3.26 17.25 6.05 39.07 3.15 17.25 6.05 IR: v = 3295, 3041, 2969, 1188, 1144, 1071, 632, 601 1595, 1562, 1478, cm ¹ 1337, 1192,

H NMR (DMSO d ₆ ): δ = 2.54 (6H, s) _{; 6/5} 4 (2H, s, interchangeable with CF3COOD); 7.03 (2H, s); 7.66-7.77 (2H, m); 7.93-7.96 (1H, m); 8.33-8.37 (1H, m); 1153 (1H, s, interchangeable with CF3COOD).

• · · · ····

Example 18 (Method A2)

N- [ 3,5-Dimethy 1 - 4- [ (nitromethy 1 ) sulfonyl 1 ] phenyl ] -4 - (methylsulfonyl ) benzenesulfonamide

1.31 ml (16.2 mmol) of pyridine, dried with potassium hydroxide, and 2.5 g (9.82 mmol) of 4-(methylsulfonyl 1 )benz ensu 1 fone 1 ch 1 o r i du are gradually added to the solution, maintained under nitrogen, and containing 1.6 g (6.55 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulfonyl]ani 1 i nu in 50 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for two hours at room temperature and poured into 200 ml of water. The aqueous solution was acidified to pH 3 by addition of 1N hydrochloric acid and extracted three times with 200 ml of ethyl acetate. The combined organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The obtained residue is purified by chromatography on a silica column (using a 2/1 methyl chloride/ethyl acetate system as an eluent) and recrystallization from a mixture of hexane and ethyl acetate, thereby obtaining 0.78 g (26% of theory) of N- [ 3.5 -dimethy 1 -4- [ (n i trometh hy 1 ) su 1 f ony 1 ] pheny 1 ]-4 - (methy 1 su 1 fonyl) benzene sulfonamide.

The melting point is 192 to 194 °C (hexane/ethyl acetate).

Elemental Analysis: CisHigNíOaSj (M = 462.50)

C% H% N% WITH% calculated 41j55 3, 92 6.06 20, 80 found 41.39 4, 02 5.90 20 _of 76 IR: V = 3281, 1597, 1586, 1555, 1485, 1401, 1395, 1366 1349, 1328, 1306, 1294, 1289, 1165, 1150, 1090, 1072

877, 860, 741, 624 cm' ¹ *Η NMR (DMSO d ₆ ): δ = 2.49 (6H, s); 3.30 (3H, s); 6.46 (2H, s, interchangeable with CF3COOD); 7/. 02 (2H, s); 8 _Of 16 (4H, s); 11.35 (1H, s, interchangeable with CF3COOD).

« · • 0 ·

Example 19 (Method A2) (E)-N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]styrenesulfonamide (E)-N-[3,5-Dimethyl-4-[(nitromethyl) sulfonyl J phenylisoprenesulfonamide is obtained by the method of Example 18 using a solution of 2.0 g (8.19 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulfonylaniline in 50 ml of tetrahydrofuran, 1.31 ml (16.2 mmol) of pyridine and 2.5 g (12.3 mmol) of trans β-styrene sulfonate 1 chI oride. The reaction mixture was stirred for three days at room temperature and extracted with methylene chloride.

The yield is 1.5 g (45% of theory).

Melting point is 174 to 176 °C (hexane/ethyl acetate).

Elemental analysis: _Ci7H18N3O5S2 ( _M = _410.45 )

C% H% N% WITH% calculated 49.74 4.42 θζ 83 15.62 to climb 50>06 4.45 θ, 84 15.35 IR: V = 3235, 1610, 1595, 1577, 1555, 1475, 1390, 1357, 1345, 1323, 1164, 1141, 1067, 889, 872, 744, 627 cm ^{1 Χ} Η NMR (DMSO d ₆ ): δ - 2.67 (6H , with) , θ, 64 (2H, with, replaces the first s CF ₃ C00D); 7.22 (2H, with) ; 7 ₇ 5 8 - 7 _of 63 (4H, m); 7.87-7.97 (3H, ni); 11,.04 (IH, with, replaces that one

’s CF3COOD) . Example 20 (Method C) 1-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-3-[(2-methylphenylsulfonyl)urine on

A solution of 0.77 ml (5.09 mmol) o-1o 1uensu1fon 1 isocyanate in 7.7 ml anhydrous methylene chloride is added dropwise to a suspension maintained under nitrogen and containing 1.3 g (5.32 mmol) of 3,5- dimethyl-4-[(nitromethyl)su1phones I}ani 1 i nu ve

4

4444 44

25.6 ml of anhydrous methylene chloride. The temperature of the reaction medium will spontaneously increase by 7 “C. Initially, a precipitate forms in the solution. Stirring was continued for one hour at room temperature and the solid was collected by filtration, washed with hexane to give 1.9 g (86% theory) of 1-[3,5dimethyl-4-[(nitromethyl)sulfonyl]pheny1 ]— 3 —[(2-methylphenyl)sulfonyl]ureas.

(Melting point is 194 to 196 “C (hexane/ethyl acetate).

fe1emen t árn i analysis: C17H19N3O7S2 (M = 441,. 47) C% N% WITH% calculate eno 46.25 4 _; 34 9.52 14.52 found 46.40 4.44 9 _; 31 14.34 IR: v = 3303, 1654, 1587, 1565, 1526 , 1455, 1393, 1362, 1341, 1326, 1164, 1153, 1131, 1089, 898, 883, 707, 606 cm' ^{1 1} H NMR (DMSO d ₆ ) ; 0 = 2.46 (6H, s); 2.58 (3H, s); 6.41 (2H, p. interchangeable with CF3COOD) ; 7.24 (2H, s); 7.38- 7.43 (2H, m); 7.52-7.57 (1H, m); 7.94 (1H, d, J =

Hz); 9.02 (IH, s, interchangeable with . CF3COOD); 11.14 (IH, pž^ ₍ interchangeable with CFsCOOD).

Example 21 (Method C) 1-[3,5-Dimethyl-4-[(nitromethylsulfonylphenyl]-3-[(4-methylphenyl)sulfonylurea)

A solution of 1.55 ml (10.2 mmol) o-to 1uens 1 phon 1 isocyanate in 15.5 ml anhydrous methylene chloride is added dropwise to a suspension maintained under nitrogen and containing 2.6 g (10.6 mmol) 3, 5-Dimethyl-4-[(nitromethyl)sulfone I]ani 1 i nu in 52 ml of anhydrous methylene chloride. The temperature of the reaction medium will spontaneously increase by 2 °C. Stirring of the obtained solution is continued for 30 minutes at room temperature. The reaction medium is evaporated to dryness under reduced pressure. The residue is purified by chromatography on a silica column (using methylene chloride as an eluent and then the system 9/1 methylene chloride/ • · · · · · * · · · 4 • * · · · · · 4 4·· 4 4 4 • « · 4 · « 4 ·

44«44··4 ·· 4 · ·· ·· methanol) and recrystallization from methylene chloride to give

2.5 g (57% of theory) of 1-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl] — 3 — [(4-methylphenyl)sulfonyl]urea.

The melting point is 150 to 155 °C.

Elemental analysis: C ₁₇ H ₁₉ N ₃ O7S ₂ (M = 441.47)

C% N%S% calculated 46.25 4.34 9.52 14.52 (found 46.40 4.44 9.31 14.12 IR: v = 1594, 1562, .1337, 1263, 1247 , 1159, 1136 cm' ^{1 Χ} Η NMR (DMSO d ₅ ): δ = 2.37 (3H, s); 2 _f 55 (6H, s); 6.45 (2H, s, replaces the first s CF3COOD) ; 7.38 (2H, d, J = 8Hz); 7.42 (2H, s); 7.83 (2H, d, J = 8 Hz) ; 9.12 (1H,

s, interchangeable with CF3COOD).

Example 22 (Method A 1 )

N-f4-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]phenyl]acetamide

2.9 g (12.4 mmol) of N-acetsulfonyl chloride is added portionwise to a mixture maintained under nitrogen atmosphere of 2.0 g (8.19 mmol) of 3,5-dimethyl-4-[{nitromethyl)sulfonyl]ani 1 inu in 40 ml anhydrous tetrahydrofuran. The reaction medium was stirred for six hours at room temperature and then refluxed for two hours, after which it was poured into 200 ml of water. The reaction mixture was extracted three times with methylene chloride, the combined organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The obtained oily residue is recrystallized by trituration from a mixture of hexane and ethyl acetate. The crystals were washed with a mixture of methylene chloride and methanol at room temperature, then with a mixture of hexane and ethyl acetate at reflux temperature, and finally with ethanol at room temperature, yielding 0.26 g (7.2

% theory) N-[4-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenylsulfamoyl]phenyl]acetamide.

The melting point is 209 to 210 C.

_Elemental analysis: _Ci7H19N3O7S2 ( _M = _441.47 )

C% H% N% WITH% calculated 46.25 4.34 9.52 14.52 found 46.25 4.43 9.78 14.25 IR: V = 3382, 3190, 1676, 1592, 1550, 1536, 1340, 1156, 1147 cm* ¹ NMR (DMSO d ₆ ): 8 = 2.10 (3H, s) ; 2.51 ( 6 Η, with) 6.48 (2H, s, interchangeable with t CF3COOD) ; 7.01 (2H, with); 7 _Of 78- 7.81 (2H, m); 7.86-7.89 ' (2H, m) ; 10.39 (1H, s, replace the first s CF3COOD) ; 11.03 (IH, s, interchangeable

with CFsCOOD).

Example 23 (Method A2)

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl)-2,2,2-trifluoroethanesulfonamide

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2,2,2trifluoroethanesulfonamide is obtained by the method of Example 18 using 1.5 g (6.14 mmol) of 3, 5-Dimethyl-4-[(ηtrimethyl)sulfonyl]aniline in 50 mL of tetrahydrofuran, 0.97 mL (12.0 mmol) of pyridine, and 1.0 mL (9.04 mmol) of 2,2,2-1-fluoroethanesulfonyl chloride. In chromatography, methylene chloride is used as an eluent.

The yield is 2.6 g (72% of theory).

The melting point is 168 to 170 °C (hexane/ethyl acetate).

Elementary ana 1 yza : CiiHi3F ₃ N ₂ O6S ₂ (M = 390.35)

C% H% F% N% WITH% calculated 33.84 3.36 14.60 7.18 16.43 for 1 month 34.14 3.44 14.25 7.35 16 _{out of} 19

·· ··

IR: V = 3227, 1601, 1564, 1351, 1333, 1323, 1270, 1248, 1157, 1147, 1135, 1089 cm ¹

NMR (DMSO d _s ): δ = 2.44 (6H, s); 4.73 (2H, q, J =

Hz); 6.39 (2H, s, interchangeable with CFyCOOD) ; 6 _? 96 (2H, s); 11.04 (1H, s, interchangeable with CF3COOD).

Example 24 i

(Method A1 )

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-4-fluorobenzenesulfonamide

1.65 g (16.5 mmol) of calcium carbonate is added to a solution of 2.0 g (8.19 mmol) of 3,5-dimethyl-4-((nitromethyl)sulfonyl-1]aniline in 40 ml of anhydrous tetrahydrofuran and, in portions of 2, 4 g (12.3 mmol) of 4-fluorobenzene chloride. The reaction mixture is refluxed for 50 hours. After cooling, it is poured into 200 ml of methylene chloride. The combined organic extracts are washed with 100 ml of water. dried over sodium sulfate and evaporated to dryness under reduced pressure. theory) of N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]-4-fluorobenzenesulfonamide.

up to 154 *C (hexane/ethyl acetate),

Ci ₅ H ₁₅ FN ₂ O ₆ S ₂ (M = 402.41)

H% F% N%

3.76 4.72 6.96

3.85 4.43 6.93

1478, 1398, 1362, 1341,

The melting point is 152 Elemental analysis:

calculated on 1ezene

C% “77 44.76

IR: v = 1592, 1563,

WITH%

15.93

15.84

1177, 1169

2 • · · « β· · · ··♦ ··· * · · · · · * ··*· «··· ·· ♦· ·· ··

1159, 1146, 1090, 1071, 877, 865, 841, 666, 635 cm ^{-1 1} Η NMR (DMSO d _s ) : δ = 2.68 (6H, s); 6.48 (2H, s, interchangeable with CF ₃ COOD); 7.18 (2H, s); 7.61-7.69 (2H, m); 8.13-8.19 (2H, m); 1131 (IH, s, interchangeable with CFaCOOD).

Example 25 (Method A2 )

N-(3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-3-fluorobenzenesulfonyl)

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-3-fluorobenzenesulfonamide is obtained by the method according to example 6 using as starting material a solution of 2.0 g (8.19 mmol) 3, 5-Dimethyl-4[(nitromethyl)sulfonylyl]in in 40 ml of tetrahydrofuran, 1.29 g (16.3 mmol) of pyridine and 2.4 g (12.3 mmol) of 3-fluorobenzenesulfonyl chloride i du. The reaction medium is stirred for two hours at room temperature and then for six hours at 40°C. The yield is 1.3 g (40% of theory).

The melting point is 135 to 137 °C (hexane/ethyl acetate).

Elemental analysis: _r _ ^c 15H ₁₅ FN2O _ě S2 (M = 402.41)

C% H% F% N% WITH% calculate eno 44.77 3.76 4, 72 6.96 15.93 to climb 44.62 3.63 4, and 65 6.91 r 16,21 IR: v = 3263, 1597, 1557, 1551, 1479, 1395, 1357, 1343, 1320, 1307, 1230, 1168, 1146, 1072, 856, 695, 676, 636, 610 cm ^{1 X} H NMR (DMSO dg ) : δ = 2.45 (6H, s); 6.43 (2H, p. replace the te1ny s CF ₃ COOD) ; 6 .97 (2H, s); 7^50-7^.73 (4H, m); 11.16 (IH, ^Ξ ' interchangeable with CFaCOOD).

Example 26 (Method A2)

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl Jphenyl]phenyl]methanesulfonamide

3 • · · · 9 9 · · ♦ · 4 • * ·· · · · · · · 4 ·*·

4 4 4 4 4 · 4 •444 »444 4» 44 4· ··

Ν-[3,5-Dimethy1-4-[(nitromthy1)sulfone 1jphenyljphenylmethanesulfonamide is obtained by the method according to example 11 using as starting material a solution of 3.0 g (12.3 mmol) of 3,5-dimethyl1 -4[(nitromethyl)sulfone 1]ani 1 i nu in 57 ml of tetrahydrofuran, 2.0 ml (24.7 mmol) of pyridine and 3.5 g (18.4 mmol) of phenylmethanesulfonyl chloride. The reaction medium was stirred for 20 hours at room temperature and then for five hours at 40°C. The final product is recrystallized from a mixture of hexane and methylene chloride.

The yield is 0.42 g (8.6% of theory).

Melting point is 124-126°C (hexane/methylene chloride). Elementary analysis. CigHxgNjOgSj (M = 398^44)

C% H% N% WITH% calculated 48.23 Δ - ) 55 7.03 ¹⁶ years 09 to climb 48,49 4 * / 59 7.03 16, 04 IR: v = 3256, 1596, 1566, 1488, 1405, 1359, 1337, 1325, 1312, 1144, 1071, 697, 638 cm' ^{1 Τ} Η NMR (DMSO dg ) : δ = 2.72 (6H, S) ; and 1.90 (2H, with) ; 6.69

(2Ή, s, ^interchangeable with CFjCOOD) ; 7.14 (2H, s); 7^497.58 (5H, m); 10.70 (1H, s, interchangeable with CF3COOD)

Example 27 (Method A2)

4-Bromo-2,5-difluoro-N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]benzenesulfonamide

1.3 g (16.4 mmol) of pyridine, dried with potassium hydroxide, and 3.6 g (12.3 mmol) of 4-bromo-2,5-difluorobenzenesulfonyl chloride are added successively to a solution maintained under nitrogen and containing 2.0 g (8.19 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulfone 1]ni 1 i nu in 40 ml of anhydrous tetrahydrofuran.

ti ti ti ti ti ti ti ti titi * • · titi ti* titi ti··*·· • ti ti ti ti ti titi ···* tititi· «· ti· «ti ··

The reaction medium was stirred for seven hours and 30 minutes at room temperature and then for 11 hours at reflux temperature. After cooling, it is poured into 300 ml of water and extracted three times with methyl chloride. The combined organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The obtained residue is purified by silica column chromatography (using methylene chloride as eluent) and recrystallization from a mixture of hexane and ethyl acetate to give 0.24 g (6.2% of theory) of 4-bromo-2,5-difluoro -N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]benzenesulfonamide containing 5% ethyl acetate.

Melting point is 167 to 169 °C (hexane/ethyl acetate).

Elemental analysis: C ₁₅ H _{i 3} BrF ₂ N ₂ O ₆ S ₂ (M = 499 31),

5% C ₄ H ₈ O ₂ ^}

C% H% Br% F% N% WITH% calculated 36.24 2.68 15.86 7.54 5.56 12.73 found 36.50 2.75 15.47 7.39 5.51 12.80 IR: V = 3242, 1565, ¹ H NMR (DMSO d _Ě ) : 1480, δ = 1350, 1167 cm” ¹ 2.42 (6H, s); 6.39 (2H, ξ

-interchangeable with CF ₃ C00D) ; 6.92 (2H, s); 7.97-8.03 (2H, m); 11.55 (1H, s, interchangeable with CF3COOD).

Example 28 (Method A2)

2,5-Difluoro-N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]benzenesulfonamide

2,5-Difluoro-N-[3,5-dimethyl-4-((nitromethyl)sulfone 1 ]pheny 1 Jbenzenes 1 fonamide is obtained by the method according to example 15 using as starting material a solution of 2.6 g ( 12.2 mmol) of 2,5-difluorobenzenesulfonide. The reaction medium is stirred for 20 hours at room temperature and then allowed to stand for ·· ι for five days. The final product is purified by silica chromatography (za using methylene chloride as an eluent) and recrystallization from toluene.

The yield is 1.1 g (32% of theory).

The melting point is 132 to 134 °C (toluene).

Elemental analysis: C _iS H ₁₄ F ₂ N ₂ O ₆ S ₂ (M = 420.40)

C% H% F% N% WITH% calculated 42 _; 85 3.36 9.04 6.66 15.25 found 43.09. 3.43 9.05 6.69 t 15.40 IR: V = 1562, 1486, 1353, 1159, 1147, 607 cm' ¹ NMR·: (DMSO d ₆ ) : δ = 2.47 (6H, with); 6 _{Out of} 44 (2H, p. from amen 11 e1ny p CF ₃ COOD) ; 6.99 (2H, s); 7.49-7.57 (1H, m); 7.60-7.64 (1H, m) ; 7.86-7.92 (1H, m)

The starting substance 2,5-difluorobenzenesulfonyl chloride is obtained as follows:

12.9 g (99.9 mmol) of 2,5-difluoride 1 is rapidly added to a mixture cooled to -10 °C in an ethanol bath, 33 ml of concentrated hydrochloric acid and 10 ml of acetic acid, followed by dropwise a solution of 7.4 g (107 mmol) of sodium nitrite in 15 ml of water. Stirring is continued for 45 minutes after the addition is complete at a temperature of -10 to -25 *C.

This solution, maintained at a temperature of approximately -25 °C, is added portionwise to a mixture, cooled to 10 °C in an ice bath, obtained by saturating 100 ml of acetic acid with sulfur dioxide and adding 2.5 g (25.3 mmol) of chloride copper. There will be a serious evolution of nitrogen. The reaction medium was allowed to warm to room temperature and maintained at this temperature for two hours, after which it was poured into 450 ml of a mixture of water and ice and extracted with ethyl ether. The combined ether extracts are washed with a saturated aqueous solution of sodium bicarbonate, dried over sulfur »9 99 • 9 9 »

9 · 9

9 9 9 999

9 #9 99

9* • 9 99 • · 9 9 * 9

9 «9··9999 • 9 * 9 » 999 • 9 9 9 9

9 9 9

9« 99 nem sodium and concentrate. The oily residue was distilled under reduced pressure to give 14.3 g (87% of theory) of a liquid consisting essentially of 2,5-difluorobenzenesulfonyl chloride, which was used in the next step without purification.

The boiling point is 65 to 70 °C/66.65 Pa.

IR: V = 3118, 3087, 1488, 1410, 1384, 1301, 1255, 1202,

1188, 1152, 1119, 1052, 881, 832, 772, 692, 689, 605,

599 cm' ¹

NMR (CDCl ₃ ) δ = 7.28-7.32 (1H, m); 7.38-7.42 (1H, m); 7.58-7.63 (IH, m)

Example 29 (Method A2)

2,3-Difluoro-N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]benzenesulfonamide

2,3-Difluoro-N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]benzenesulfonamide is obtained by the method according to example 15 using as starting material 2.6 g (12.2 mmol) 2.3 -difluorobenzenesulfonyl chloride. The reaction medium was stirred for 20 hours at room temperature in the absence of light and allowed to stand for three days before working up. The final product is purified by silica column chromatography (using methylene chloride as eluent) and recrystallization from toluene.

The yield is 1.1 g (32% of theory).

The melting point is 166 to 168 °C (toluene).

Elemental analysis: C15H14F2N2O6S2 (M = 420.40) calculated found

C% H% F% N% WITH% 42.85 3.36 9.04 6.66 15.25 43.07 3.51 8.98 6.61 15.01

*

IR: v = 3292, 1600, 1557, 1494, 1363, 1348, 1329, 1276,

1199, 1161, 1140, 636 cm' ¹

NMR (DMSO d ₆ ): δ = 2.29 <6H, s); 6.28 (2H, S, ' interchangeable with CF ₃ COOD) ; 6.81 (2H, s); 7.24-7.29 (1H, m); 7.61-7.67 (2H, m); 11.44 (IH, s, interchangeable with CF3COOD).

The starting substance, 2,3-difluorobenzenesulfonyl chloride, is obtained by the method described in Example 28 using either 22 ml of concentrated hydrochloric acid, 7.7 ml of acetic acid, 10.0 g (77.5 mmol) of 2,3-difluoroaniline 1 and 5.8 g (84.1 mmol) of sodium nitrite in 12 ml of water, 1 ml of acetic acid saturated with sulfur dioxide and 1.9 g (19.2 mmol) of copper chloride. The yield is 8.5 g (52% of theory).

The boiling point is 60 to 80 °C/66.65 Pa.

IR: v = 1606, 1493, 1388, 1280, 1238, 1203, 1171, 1148,

907, 824, 789, 711, 650 cm' ¹

NMR (CDCl 1 ): δ = 7.37-7.42 (1H, m); 7.61-7.65 (IH,

m); 7.76-7.81 (IH, m)

Example 30 (Method A2)

3,5-Difluoro-N-[3,5-dimethyl-4-[(nitromethy1)sulfonyl]phenyl]benzenesulfonamide

3,5-Difluoro-N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl 1 ]benzene 1-fonamide is obtained by the method according to example 15 using as starting material 2.6 g (12.2 mmol ) 3,5-difluorobenzenesulfonate, which is added as a solution in 20 ml of tetrahydrofuran. The reaction medium was stirred for 20 hours at room temperature in the absence of light and allowed to stand for three days before working up. The final product is purified by silica column chromatography (using methylene chloride as eluent) and recrystallization from toluene.

The yield is 1.8 g (52% of theory).

The melting point is 187 to 190 °C (toluene). Elemental analysis: Ci ₅ H ₁₄ F ₂ N ₂ O6S ₂ (M = 42CH40)

C% H% F% N% WITH% calculated 42.85 3.36 9, 04 6.66 15.25 to climb 43.21 3.44 8, 85 6.50 15.01 IR: V = 3343 , 2979, 1607, 1595, 1555, 1474, 1446, 1401, 1363, 1346, 1316, 1295, 1252, 1196, 1160, 1127, 1070,

993, 801, 668, 637, 616 cm ^{4 X} H NMR (DMSO d _s ): δ = 2.45 (6H, s); 6.42 (2H, s, interchangeable with CF ₃ CO0D); 6.97 (2H, s); 7.57-7.64 (3H, m); 11.21 (ÍH, s, interchangeable with CF3COOD).'

The starting substance, 3,5-difluorobenzenesulfonyl chloride, is obtained by the method described in Example 28, using either 22 ml of concentrated hydrochloric acid, 7.7 ml of acetic acid, 10.0 g (77.5 mmol) of 3,5-difluorobenzene 1 i nu and 5.8 g (84.1 mmol) of sodium nitrite in 15 ml of water, 77 ml of acetic acid saturated with sulfur dioxide and 1.9 g (19.2 mmol) of copper chloride. The yield is 7.1 g (43% of theory) as a white solid. Boiling point 60 to 120 °C/66.65 Pa.

IR: V = 3100, 1608, 1592, 1446, 1375, 1361, 1301, 1178,

1133, 1080, 992, 881, 866, 662, 611 cm ^{-1 ς} Η NMR (CDCl ₃ ): δ = 7.04-7.11 (1H, m); 7.46-7.48 (2H, m)

Example 31 (Method A2)

N-[3,5-Dimethyl-4-[(nitromethylsulfonyl]-1-phenyl]-1-naphthalene sulfonamide

N-[3,5-Dimethyl-4-[{nitromethylsulfonyl]phenyl]-1-naphthalene sulfonamide is obtained by the method of Example 15 using 2.8 g (12.4 mmol) of 1-naphtha as starting material Iensu1fony 1ch1 oř i du. The reaction medium was stirred for 26 hours at room temperature. The final product is purified by silica column chromatography (using methylene chloride as eluent) and recrystallization from toluene.

The yield is 1.4 g (39% of theory). The melting point is 170 up to 172 °C (toluene). Elemental analysis: Ci ₉ H ₁₈ N ₂ O _è S2 (M = 434 _y 47) C% H% N% WITH% calculate no 52.52 4.18 6.45 14.76 found 52.65 3.89 6.51 14.72 IR: V = 3267, 1595, 1560, 1330, 1181, 1163, 1136, 1070

771, 636, 600 cm ^-1

NMR (DMSO d ₆ ) : δ = 2.44 (6H, s); 6.42 (2H, s, interchangeable with CF3COOD); 6.95 (2H, s); 7.68-7.83 (3H , m) ; 8 _f 13 (ÍH, d, J = 8.0 Hz); 8.31 (ÍH, d, J = 8 _; 2 Hz) ; 8.46 (ÍH, d, J = 7.3 Hz); 8.70 (ÍH, d, J = θ, ⁵ Hz) ; 11.53 (ÍH, with, interchangeable with CF3COOD).

For k1 ad 3 2 (Method A2)

N-f 3,5-Dimethhy1-4-[(nitromethylsulfonyl]phenyl]-2-thiophenesu1f onam i d

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2-thiophenesulfonamide is obtained by the method according to Example 6 using as starting material a mixture of 3.0 g (12.3 mmol) of 3,5- dimethyl 1-4-[(nitrometh hy 1 ) su 1 fony 1 ] an i 1 i nu , 60 ml of tetrahydrofuran and 1.95 ml (24.1 mmol) of pyridine, to which 2.8 g (15.3 mmol ) of 2-thiophenesulfonyl chloride. The reaction medium was stirred for 24 hours at room temperature and heated to 50°C for four hours. The final product is purified by silica column chromatography (using methylene chloride as eluent) and recrystallization from toluene. The yield is 0.8 g (17% of theory).

The melting point is 158 to 159 °C (toluene).

Elemental analysis: Ci ₃ H ₁₄ N ₂ O ₆ S ₃ (M = 390.44)

) C% H% N% WITH% calculated 39 _} 99 3.61 7.18 24.63 found 40, 07 3.68 7.29 24.46 IR: v = 1598, 1552, 1345, 1151, 600 cm' ^{1 ς} Η NMR (DMSO d _e ) : δ = 2.36 (6H, with) 6.33 <2H, with, interchangeable with CF3COOD) ; 6.90 (2H, s); 7.02-7.04 (IH, m) ; 7.63-7^65 (IH, m) ; 7.83-7 _of 85 (IH, m); ll _of 09

(IH, s, interchangeable with CFsCOOD).

Example 33 (Method B)

N-[4-[(Dichlorotrimethyl)sulfonyl]-3,5-dimethylphenyl]benzenesulfonami d

A mixture of 0.96 g (2.50 mmol) N-[3,5-dimethyl 1-4-[(nitromethyl lis 1 phon 1 ] pheny 1 ] benzene 1 phonami du , O, 66 g (4.94 mmol) N-chlorosuccinimide and 10 mg (0.06 mmol) of 2,2'-azobisisobutyronitrile in 20 ml tetrachloromethane were refluxed for six hours.After cooling, the insoluble fraction was filtered off and the solution was evaporated to dryness under reduced pressure the residue is purified by chromatography on a column of silica (using methylene chloride as an eluent) and recrystallization from a mixture of hexane and methylene chloride, whereby 0.28 g (25% of theory) of N-[4-[(dichloronitromethyl)sulphone 1]51 is obtained * · * · · · 4 4 · 4 » • »······ 444 ··· « 4 4444 · 4

44444444 «4 44 44 4

of 3,5-dimethylphenyl]benzenesulfonamide.

Melting point is 112 to 114 °C (hexane/methylene chloride) Ci5Hi4Cl ₂ N2O ₆ S ₂ (M = 453.31)

39 _; 74

40.24

H%

3,H 3.20

Cl%

15.64

15.71

N% _f 18 6.29

WITH%

14.14 13.70

Elemental analysis:

C% calculated on 1ezene

IR: V = 3218, 1580, 1466, 1360, 1329, 1310, 1186, 1161, >1091, 748, 618, 609, 601 cm' ¹

NMR (DMSO d ₅ ): δ = 2.38 (6H, s); 7.00 (2H, s); 7,497.59 (3H, m); 7.81-7.84 (2H, m); 11.29 (1H, s, interchangeable with CF3COOD).

Example 34 (Method A2)

N-[3,5-Dimethyl]-4-[(nitromethylsulfonyl]phenyl]-2-fluorobenzenesulfonamine 1d

1.29 g (16.3 mmol) of pyridine, dried over potassium hydroxide, and 2.4 g (12.3 mmol) of 2-fluorobenzenesulfonyl chloride are added rapidly and gradually to a solution, maintained under nitrogen, containing 2.0 g (8.19 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulfonyl]aniline in 40 ml of anhydrous tetrahydrofuran. The reaction medium was stirred for two hours at room temperature and then kept at 40°C for 12 hours. After cooling, the reaction medium is poured into 100 ml of water and 100 g of ice, acidified with 1N hydrochloric acid to pH 2 and extracted three times with 100 ml of methylene chloride. The combined organic extracts were washed with 100 ml of water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The pasty residue is purified by silica column chromatography (using methylene chloride as eluent) and recrystallization from a mixture of hexane and ethyl acetate to give 1.5 g of {46 • »

*·

4 4

4 4 >4 4 Ů ··44 44· % theory) of N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2fluorobenzenesulfonamide.

The melting point is 175 to 177°C (hexane/ethyl acetate).

Elemental analysis: C _l5 H ₁₅ FN ₂ O ₆ S2 (M = 402.41)

C% H% F% N% WITH% calculated 44.77 3.76 4, / 72 6.96 ¹⁵ ; 15, 93 found 44.99 3.61 66 6.95 81 IR: V = 3236 , 1598, 1583, 1557, 1475, 1390, 1350, 1329, 1191, 1175, 1160, 1149, 1124, 1077, 1068, 890, 881,

875, 778, 623, 600 cm ^{1 T} H NMR (DMSO d ₆ ): δ = 2.56 (6H, s); 6.55 (2H, s, interchangeable with CFjCOOD) ; 7.08 (2H, s); 7.51-7.56 (2H, m); 7.84-7.87 (1H, m); 8.11-8.16 (1H, m); 11.55 (1H, s, interchangeable with CFsCOOD).

Example 35 (Method A2)

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-4-(trifluoromethyl)benzenesulfonamide

N-[3,5-Dimethyl-4-((nitromethyl)sulfonyl]phenyl]-4-(trifluoromethyl)benzenesulfonamide is obtained by the method of Example 34 using as starting material 3.0 g (12.3 mmol) of 4-(trifluoromethyl)benzenesulfonyl chloride. The reaction mixture was stirred for two hours at room temperature and then heated to 40°C for 20 hours.

The yield is 1.5 g (35% of theory).

Melting point is 187-188°C (hexane/ethyl acetate).

Elemental Analysis: „ „ ~ _KT „ _

C16H15F3N2O5S2 (M = 452.42)

C% H% F% N% WITH% calculate eno 42,47 3.34 12.60 6.19 14,17 for 1 month 42.73 3.39 12.42 6.13 14.00

IR: v = 3252, 1596, 1563, 1408, 1347, 1324, 1166, 1140,

1131, 1092, 1062, 751, 638 cm ^{1 X} H NMR (DMSO dg ) : δ = 2 32 (6H, s); 6 f 40 (2H, with, replace the first s CF3COOD) ; 6.95 (2H, s) ; 7 ' ,95 (2H, d, J = 8.4 Hz); 8.05 (2H, d, J = 8.3Hz); 11 ,26 (IH, Ξ , from names i t e1ný s CF ₃ C00D) . C% H% F% N% WITH% calculated 37.98 2.34 20 ,03 5 , 91 13 _t 52 , for climbing 37.94 2.38 19 ,65 5, 75 13.40 'IR: v = 1563, 1522, 1503, 1330, 1170, 1142, 992 cm' ^{1 X} H NMR (DMSO d _s ) : δ = 2, 49 (6H, s); ⁶ / 50 (2H, Ξ, - z amen i t e1ný s CF ₃ C00D); 7.03 (2H, p ) ; 12, 1

pik/ interchangeable with CF3COOD).

Example 38 (Method A2)

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2-dibenzofuransuIf onamide

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2-dibenzofuransulfonamide is obtained by the method according to example 6 using as starting material a solution of 2.0 g (8.19 mmol) 3, 5-Dimethyl 4-[(nitromethy1)sulfone 1]an i 1ine in 38 ml tetrahydrofuran, 1.3 ml (16.1 mmol) pyridine and 3.3 g (12.3 mmol) 2-dibenzofuransulfone chloride (prepared by the method described by M. Janczewski and H. Maziarczyk, Rocz. Chem. 47 (11), pp. 2055-2069, 1973). The reaction medium was stirred for 20 hours at room temperature and then heated to 45°C for four hours. The final product is purified by silica column chromatography (using methylene chloride as eluent) and recrystallization from a mixture of hexane and ethyl acetate.

The yield is 0.48 g (12% of theory).

Melting point is 214 to 215 °C (hexane/ethyl acetate) (decomp.).

Elementary ana 1 yza : C ₂ iHiaN ₂ O7S2 (M = 474.49)

C% H% N% WITH% calculated 53 J ¹⁵ 3.82 5.90 13.51 to climb 52 ,88 3.91 5.92 13.46

_IR; ^{, 611 cm' 1} _* Η NMR (DMSO d ₆ ): δ = 2.41 (6H, s); 6^36 (2H, s, interchangeable with CF ₃ COOD) ; 7.00 (2H, s); 7.43 (1H, t, ; J = 7.2 Hz); 7.53-7.59 (1H, m); 7.72 (1H, d, J = *8.3 Hz); 7.88 (1H, d, J = 8.7 Hz); 7.95 - 7.99 (1H, m);

8.32 (1H, d, J = 7.3 Hz); 8.82 (1H, d, J = 1.9 Hz); 11.10 (IH, s, interchangeable with CF3COOD).

Example 36 (Method A2)

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonylphenyl]-4-{trifluoromethoxy)benzenesulfonamide

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonylphenyl]-4-(trifluoromethoxy)benzenesulfonamide is obtained by the method of Example 11 using as starting material a solution of 3.1 g (12.7 mmol ) 35-Dimethyl-4-[{π itromethyl)sulfone 1]ani 1 i nu in 62.4 ml tetrahydrofuran, 2.05 g (25.9 mmol) pyridine and 5.0 g (19.2 mmol) 4- (trifluoromethoxy)benzenesulfonyl chloride.

The yield is 1.8 g (29% of theory).

The melting point is 180 to 182°C (hexane/ethyl acetate). Elemental analysis: Ci ₆ H ₁₅ F ₃ N ₂ O7S ₂ (M = 468.42)

C% H% F% N% WITH% calculated 41.02 3.23 12,17 5.98 13.69 found 41.06 3.29 11.81 6.13 13.41 IR: V = - 1595, 1559, 1347, 1327, 1266, 1218, 1164, 1138 cm' ^{1 Χ} Η NMR (DMSO d _s ) : δ = 2.34 (6H, with) 6 ,31 (2H, p.

interchangeable with CF3COOD) J = 8.2 Hz);

interchangeable with CF3COOD)

6.85 (2H, s (2H, m);

7.47 (2H, d, (1H,

7.87-7.92

11, 07

Ξ, »· · · an 99

Example 37 (Method A1 )

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2,3,4,5,6-pentafluorobenzenesulfonamide

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2,3,4,5,6pentafluorobenzenesulfonamide is obtained by the method according to Example 5 using as starting material a solution of 1.3 g (5.32 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulfonyl]aniline in 50 ml of tetrahydrofuran, 1.1 g (11.0 mmol) of calcium carbonate and 2.1 g (7.88 mmol) of pentafluorobenzenesulfonyl chloride. The reaction mixture was stirred for 68 hours at room temperature. The final product is purified by silica column chromatography (using methyl chloride as eluent).

The yield is 0.4 g (16% of theory).

Melting point is 128 to 130 °C (hexane/methylene chloride)

Elemental analysis: Ci s Hi i Fs N ₂ Oe S ₂ (M = 474.37)

Example 39 (Method A2)

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-4-biphenylsulfonamide

N-[3,5-Dimethy1-4-[(nitromethyl)sulfonyl]phenyl]-4-biphenylsulfonamide is obtained by the method according to Example 6 using as starting material a solution of 2.0 g (8.19 mmol) of 3.5 -dimethyl-4-[(nitromethyl)sulfone 1]ani 1 i nu in 38 ml tetrahydrofuran, 1.3 ml (16.1 mmol) pyridine and 3.1 g (12.3 mmol) 4-biphenylsulfone 1 chloride. The reaction mixture was stirred for 20 hours at room temperature and heated to 40°C for four hours. The final product is purified by chromatography on a silica column (using methylene56 *· ι 44 a « a· 4 chloride as an eluent) and recrystallization from a mixture of hexane and ethyl acetate. The yield is 0.68 g (18% of theory).

Melting point is 206 to 208°C (hexane/ethyl acetate) (decomp.).

Elemental analysis: C21H20N2O6S2 (M = 460.51)

C% H% N% WITH% calculate eno 54.77 4.38 6.08 13 _; 92 (found 54.90 4.43 7 6.05 13 _of 58 · IR: V = 3237, 1594, 1564, 1557, 1479, 1346, 1156, 1068, 764, 674, 626, 604 cm ^{-1 LK} NMR (DMSO d ₅ ): δ = 2.53 (6H, with) 6.49 (2H, s, replace the first s CFaCOOD) ; 7.08 (2H, s); 7.48-7.57 (3H, m); 7.75-7.78 (2H, m) ; 7.94- 8.04 (4H, m) ; 11.20

(1H, s, interchangeable with CF3COOD).

Example 40 (Method A2)

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]methanesulfonamide

A solution of 1.7 g (14.8 mmol) of methanesulfonyl chloride in 5 ml of anhydrous tetrahydrofuran was added dropwise to a solution, maintained under nitrogen, containing 2.7 g (11.0 mmol) of 3,5-dimethyl-4-[ (nitromethyl)sulfone and 1.6 g (20.2 mmol) of pyridine, dried over potassium hydroxide, in 50 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred for six hours and 30 minutes at room temperature and then refluxed for four hours. 1.1 g (9.60 mmol) of methanesulfonyl chloride was added and reflux was continued for an additional hour and 30 minutes. An additional 1.1 g (9.60 mmol) of methane chloride is added and reflux is continued for another four hours. After cooling, the reaction mixture is poured into ice-cold water and ««*»···· * « * * extracted with methylene chloride. The combined organic extracts were dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was recrystallized from a cooled mixture of hexane and methylene chloride and purified by recrystallization from a mixture of hexane and ethyl acetate to give 1.1 g (22% of theory) of N-[3-5-dimethy latini trome t hy 1 )su 1 phon 1 ] phen 1 ] methane 1 phonamide containing 14 mol% ethyl acetate.

(Melting point is 138 to 140 °C (hexane/ethyl acetate).

Elemental Analysis: SiOH^^OgSi (M = 322.35), 14% C4HSO2

C% H% N% WITH% calculated 38 _f 18 4.61 8.32 19.05 to climb 37.90 4.55 8,12 18.62

IR: V = 3269, 1598, 1569, 1344, 1339, 1309, 1142 cm' ^{1 X} H NMR (DMSO d ₆ ): δ = 2.58 (6H, s); 3.23 (3H, s); 3.5 (1H, pkg., interchangeable with CF3COOD) ; 6.52 (2H,

S/ interchangeable with CF3COOD) ; 7.09 (2H, s).

Example 41 (Method C)

-[3,5-Dimethyl-4-[(nitromethyl 1 )sulfonyl]phenyl] - 3-(phenylsulfonyl)urea

-[3,5-Dimethyl-4-f(nitromethyl)sulfonyl]phenyl]-3-(phenylsulfonyl)Urea is obtained by the method of Example 20, using as starting material a suspension of 2.8 g (11 .5 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulfone 1]ani 1 i nu in 56 ml of methylene chloride and a solution of 2.0 g (10.9 mmol) of benzene 1 phony 1 isocyanate in 15 ml of methylene chloride ethyl acetate is removed from the final product by refluxing in methylene chloride for two hours.

The yield is 4.5 g (96% of theory).

The melting point is 140 to 142 °C (hexane/ethyl acetate).

• · ·· • *·** «·* *«· • · · * · * » * ···· ···» ·« 0* «φ ·»

Elemental analysis: C ₁₆ Hi ₇ N ₃ O ₇ S2 (M = 427.44)

C% H% N% WITH% calculated 44, 96 ⁴ , 01 9.83 15.00 to climb ⁴⁵ / 15 ⁴ , 16 10.15 14.71 IR: V = 1658, 1587, 1567, 1529, 1463, 1326, 1152, 1086, 899 cm' ¹ NMR (DMSO d ₆ ) : δ = 2.31 (6H, s); 6. 26 (2H, with,

exchchangeable with CF-jCOOD); 7.09 (2H, s); 7.41-7.54 (3H, m); 7.76-7.79 (2H, m); 9.06 (1H , s, from amenit e1ny is CF3COOD) _; 10.96 (1H, Blue p^h, interchangeable with CFsCOOD).

Example 42 (Method A2)

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]-3-dibenzofuransulfon]amide

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]-3-dibenzofuransulfon]amide is obtained by the method according to Example 6 using as starting material a solution of 2.0 g (8.19 mmol) of 3.5 -dimethy1-4-[{nitromethy1)su1fony 1]ni 1 i nu in 40 m! tetrahydrofuran, 1.29 g (16.3 mmol) of pyridine and 3.0 g (12.3 mmol) of 3-dibenzofuran-1-phenyl chloride (prepared by the method described by M. Janczewski and H. Maziarczyk, Rocz. Chem. 48 (11), pp. 1907 to 1919, 1974). The reaction medium was stirred for two hours at room temperature and then heated to 40°C for 24 hours. The final product is purified by chromatography on a column of silica (using methylene chloride as eluent) and recrystallization from a mixture of hexane and ethyl acetate. The yield is 2.1 g (54% of theory).

Melting point 206-208°C Elemental analysis: C 2 iHigN ₂ O ₇ S ₂ C% calcd 53 ₁₅ found (hexane/ethyl acetate). (M = 474 _; 49)

H% N% 3.82 5.90 3.95 5?68

* ···

IR: v = 3274, 1592, 1561, 1462, 1343, 1324, 1201, 1180,

1158, 1139, 1068, 852, 745, 705, 653, 632 cm' ^{1 1} H NMR (DMSO d ₆ ): δ = 2.52 (6H, s); 6.46 (2H, s, interchangeable with CF3COOD); 7.09 (2H, .s); 7.53-7.55 (IH, m); 7.69-7.72 (IH, m); 7.84 (IH, d, J = 8.3 Hz);

96-8.00 (ÍH, m) ; 8.28-8.33 (2H, m); 8.44 (ÍH, d, 'T

J = 8.1 Hz); 11.25 (1K, s, interchangeable with CFsCOOD).

Example 43 (Method A1)

N-[2-Chloro-4-[3,5-dimethyl-4''((nitromethyl)sulphone 1Jphenylsulfamoy1Jphenylacetamide

N-[2-Chloro-4-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenylsulfonyl]phenyl]acetamide is obtained by the method according to Example 22 using as starting material 3.3 g (12.3 mmol) of 4- of acetamido 3-chlorobenzenesulfonyl chloride. The reaction medium was stirred for seven hours 30 minutes at room temperature and then refluxed for seven hours 30 minutes. The obtained solid residue after concentration under reduced pressure was triturated from hexane and washed with a mixture of hexane and ethyl acetate and finally washed with ethanol.

The yield is 0.1 g (2.6% of theory). Melting point is 209 up to 211 'C. E1emen t ary analysis ^: C ₁₇ H ₁₈ C 1 N ₃ O ₇ S ₂ (M = 475.92) C% H% Cl% N% WITH% calculated 42.90 3, 81 7.45 8.83 8.77 13.47 13.01 to climb 42.75 3, 91 7.75 IR: V = 3402, 3276 , 1722, 1583, 1550, 1514, 1349, 1174,

1163, 631 cm' ¹

• * 0 «00» 0 * » • ···» 0 · 0 · 0 0 · 0 · 0 « 0 0 0 0 · 0 ^r H NMR (DMSO d ₆ ) : 5 = 2.04 (3H, s) ; 2.39 (6H, with) 6, 3 6 (2H, s, interchangeable with CF3COOD); 6.90 (2H, with); 7.74 (1H, dd, J = 8.7 and 2 2 Hz); 7 _? 86 (1H, d, J = 2.2 Hz); 8 _; 01 (1H, d, J = 8 _Z 7 Hz); 9 _Of 64 (1H, s, replace the first 5 as well

with CF3 COOD).

Pri k1 ad 44 (Method A2)

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2-methoxybenzenesulfonami d

N-(3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2-methoxybenzenesulfonyl]amide is obtained by the method according to example 18 using as starting material a solution of 2.0 g (8.19 mmol) of 3, 5-Dimethyl-4-((nitromethyl)sulfone 1]ani 1 i nu in 50 ml of tetrahydrofuran, 1.31 ml (16.2 mmol) of pyridine and 2.53 g (32.2 mmol) of 2-methoxybenzenesulfonyl chloride (prepared by , described by H. Meerwein, Chem. 90, pp. 841-852. The final product is purified by silica column (using methylene chloride as eluent).

The yield is 1.8 g (53% of theory).

calculated found

up to 174 ’C (hexane/ethyl acetate) CisH _ia N ₂ O7S2 (M = 414.44) C% H% N% WITH% 46,37 4.38 6.76 15.47 46.34 4.29 6.74 15.29

IR: V = 3261, 1595, 1559, 1486, 1335, 1323, 1282, 1166, 1157, 1132, 1072, 600 cm' ^{1 Χ} Η NMR (DMSO d ₆ ) : δ = 2.59 (6H, s); 3.98 (3H, s); 6.57 {2H, s, interchangeable with CFACOOD) ; 7.10 (2H, s); 7,237.29 (1H, m); 7.34 (1H, d, J = 8.1 Hz); 7.74-7.80 (1H, m); 8.06-8.09 (1H, m); 10.99 (1H, s, interchangeable with CFaCOOD).

* * ♦ · ·· 9 9

Example 45 (Method A2)

N-[3,5-Dimethyl-4-[(nitromethylsulfonyl]phenyl]-2-methylbenzenesulfonamide

N-[3,5-dimethyl-4-[(nitromethylsulfonyl]phenyl]-2-methyl 1 (benzenesulfonamide) is obtained by the method of Example 27 using as starting material a solution of 2.6 g (10.6 mmol) 3 ,5-Dimethyl-4-[(nitromethyl)sulfone 1]ani 1 i nu in 65 ml of tetrahydrofuran,

1.69 mL (20.9 mmol) of pyridine and 3.0 g (15.7 mmol) of ortho-toluenesulfonyl chloride. The reaction mixture was stirred at room temperature for 24 hours and then heated to 40°C for eight hours and then left for 24 hours at room temperature.

The yield is 0.29 g (6.8% of theory).

The melting point is 118 to 120 °C (hexane/ethyl acetate).

Elemental analysis: _C i ₆ H ₁₃ N ₂ O _with S ₂ (M = 398.44)

C% H% N% WITH% calculated 48.23 4.55 4.40 7.03 16.09 for 1 month 48 _years 37 7,10 15.77

NMR analysis indicates the content of the ortho-methyl isomer (approx. 50%), mixed with the meta-isomers and with the para-isomer (approx. 50% combined), since commercial ortho-toluenesulphonyl chloride (TC1) is actually a mixture of isomers (as evident from its NMR spectra).

Example 46 (Method A2)

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-3-meth oxybenzenesulfonami d • ti ti ti • tititi ti ti ti ti • tititi • ti 4 • ti <

* titi ti • titi · • ti ti *»· • ti • ti titi

N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-3-methoxybenzenesulfonyl]amide is obtained by the method according to example 2 using 2.0 g (8.18 mmol) of 3 as starting material, 5-Dimethyl-4-[(nitrimethyl)sulfonyl]aniline in 50 ml of tetrahydrofuran, 1.30 ml (16.1 mmol) of pyridine and 2.50 g (12.3 mmol) of 3-methoxybenzenesulfonyl chloride (prepared by the method described by M. Ludwig et al., Collect. Czech. Chem. Commun. 49, p. 1182, 1984).

(The yield is 0.83 g (24.7% of theory).

Melting point is 166 to 168 °C (hexane/ethyl acetate).

Elemental analysis: Ci ₆ Hi ₈ N ₂ O7S ₂ (M = 414.44) WITH% C% H% N% calculated 46,37 4.38 6.76 15.47 to climb 46,37 4.48 6.70 15.31 ^LK NMR (DMSO d ₆ ) : δ = 3 .85 (3H, with) 6.5 (2H, s, interchangeable with CF ₃ COOD) ; 7.05 (2H, with) 7.25 to 7.65

(4H, m); 11.1 (1H, s, interchangeable with CF3COOD).

Example 47 (Method Al )

N -[ 3 , 5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-3-pyridine sulfonamide

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-3-pyridinesulfonamide is obtained by the method according to example 5 using 1.7 g (7 mmol) of 3 as starting material, 5-Dimethyl-4-[(nitromethyl)sulfones 1]ani 1 i nu, 40 ml tetrahydrofuran, 2.80 g (28 mmol) calcium carbonate 1.9 g (10.5 mmol) 3-pyridine sulfone 1 chloride (prepared by the method, which was described by Fuerst et al., J. Prakt. Chem. 36, p. 160, with stirring for five hours at room temperature. The crude product is chromatographed on silica eluting with methylene chloride/methane 1 (98:2) and recrystallized from hexane/ethylation mt.

The yield is 0.11 g (4% of theory).

Melting point is 191-192°C (hexane/ethyl acetate). Elemental analysis: Ci ₄ Hi ₅ N ₃ O ₆ S2 (M = 385.42)

C% H% N% WITH% calculated 43.63 3.92 10.90 16.64 found 43.62 3, 99 10.91 16.76 NMR (DMSO d _s ) : δ = 6.5 (2H, s, replace i t e1ny s CF3COOD) ; 7.03 (2H, with); 7.64 (IH, dd); 8.28 (1H, dt); 8.85 (1H, dd); 9.06 (1H, d) ; 11.3 (IH, p. from names and t e1ny

with CF3 COOD).

Example 48 (Method A2)

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-(2-trifluoromethylphenyl)methanesulfonamide

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl-3-phenyl]-(2-trifluoromethyl-phenyl)-methanesulfonamide is obtained by the method according to Example 2 using 3 g (12.28 mmol) of 3,5-dimethyl- 4-Γ(nitromethyl)sulfonyl]aniline, 57 mL of anhydrous tetrahydrofuran, 2 mL (24.7 mmol) of pyridine, and 4.8 g (18.5 mmol) of (2-trifluoromethylphenyl)methanesulfonyl chloride (prepared as described by Hamer et al. coll., J. Pharm, Sci. 64, p. 1961, 1975 ). The product obtained is recrystallized from the hexane/ethyl acetate system.

The yield is 1.37 g (24% of theory).

The melting point is 146 to 148 °C (hexane/ethyl acetate). E1ementary analysis: C17H17F3N2O6S2 C% F% N% WITH% calculated 43.77 3.67 12,22 6.01 13.75 found 43.72 3.90 11.97 6.03 13,.65

• φ φ φ ·· • φ * · ·*·* »··· ·· · ·« « * « ·· »· ^Χ Η NMR (DMSO d ₆ ) : δ = 2.3 (6Η, s); 4.6 (2Η, s); 6.27 (2Η, s, interchangeable with CF3COOD); 6.71 (2Η, s); 7 _Ζ 4 to 7.6 (4Η, m); 10.6 (IH, s, interchangeable with CF3COOD).

Example 49 í

('Method A2 )

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl Jphenyl]-(3-fluorophenyl)methanesulfonamide

N-[3,5-Dimethyl-4-[(nitromethyl)sulfone 1J-phenyl-J-(3-fluorophenyl)methanesulfonamide is obtained by the method according to example 2, using 3 g (12.28 mmol) of 3,5-dimethyl- 4[(nitromethyl)sulfonyl]ani 1 i nu , 57 ml of anhydrous tetrahydrofuran, 2 ml (24.7 mmol) of pyridine and 3.85 g (18.4 mmol) of (3-fluorophenyl)methane 1fone 1ch1oride (prepared by the method described in US Patent No. US 3,471,474). The product obtained is recrystallized from the hexane/ethyl acetate system.

The yield is 0.45 g (8.8% of theory).

Melting point is 172 to 174 °C (hexane/ethyl acetate).

Elemental analysis: C ₁₇ H _i7 FN ₂ O _with S ₂ (M = 416.45)

calculate eno C% H% F% N% WITH% found 46.15 4.11 4.56 6.73 15.40 45^96 4.05 4.62 6.73 15/44

NMR (DMSO d _e ): δ = 2.28 (6H, s); 4.5 (2H, with); 6.24 (2H, s, interchangeable with CF3COOD) ; 6.71 (2H, with); 6.85 it 7.0 (3H, m); 7.11 - 7.21 (1H, m); 10,.25 (IH, with, interchangeable with CF3COOD).

·· ·· ·· «· 99 99 • * · · ««· 9 9 · « • * 9 9 9 9 9 9 «9 9 • 9 · · 9 9 99 999 99« • 9 «999 9 9

9999 9999 99 99 99 99

Example 50 (Method A2 )

Ν-[3-[[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenylamino]sulfonyl]phenylacetamide

N-[3-[[3,5-Dimethyl-4-[(nitromethyl)'sulfonyl]phenylamino]sulfonyl]phenyl]acetamide is obtained by the method of Example 2 using 2 g (8.18 mmol) as starting material 3,5-dimethyl-4[nitromethyl]sulfone, 50 ml of anhydrous tetrahydrofuran, 1.3 ml (16.1 mmol) of pyridine and a solution of 3.8 g (16.2 mmol) of 3-acetylaminobenzenesulfonyl chloride (prepared by the method described by Barco et al., Synthesis, p. 877, 1974) in 50 mL of anhydrous tetrahydrofuran. After evaporation of the extraction solvent, the residue is chromatographed on silica using hexane and ethyl acetate (1:1) as an eluent and recrystallized twice from methylene chloride.

The yield is 0.775 g (21.4% of theory).

The melting point is 108 to 110 °C (methy1ench1oride),

Elemental analysis: C17H19N3O7S2 (M = 441.48) WITH% C% H% N% calculated 46.25 4.34 9.52 14.53 found 46.15 4.5 9.29 14,17 ^ς Η NMR (DMSO d _s ) : δ = 2.08 (3H, s) ; 2.48 (6H, s); 6 45 <2H, with, interchangeable with CF ₃ C00D); 7.0 (2H, s); 7.5 it 7.7 (3H, m); 8.36 (IH, s) ; 10.3 (1H, s, z ame n i t e1ny with CFaCOOD) ; 11,15 (ÍH, p 'swap i t elny s CF3COOD).

Example 51 (Method A2)

N-[3,5-Dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-(2-methylphenyl)methanesulfonamide »4 4 44 β

4444 4«44 • 4 4 ·♦· 4 4 4 4

Ν-[3-[[3,5-Dimethyl-4-[(nitromethyl-sulfonyl-phenyl]-(2-methyl-phenyl)-methanesulfonamide is obtained by the method of Example 2 using 2 g (8.18 mmol) 3.5 -dimethyl 1-4-[(nitromethyl)sulfones, 38 ml of anhydrous tetrahydrofuran, 1.3 ml (16.1 mmol) of pyridines and 2.5 g (12.2 mmol) of (2-methylphenyl)methanesulfone chloride After evaporation of the extraction solvent, the residue is chromatographed on silica using first methylene chloride and then hexane and ethyl acetate (1:1) as eluent.

Finally, the product is recrystallized from the hexane/ethyl acetate system. The yield is 0.19 g (5.6% of theory).

Melting point is 167 to 169 °C (hexane/ethyl acetate).

Elementary ana 1 yza : Ci7H ₂₀ N ₂ OáS ₂ (M = 412.49)

C% H% N% calculated 49, 50 4.89 73 4.90 6.79 to climb 49, 6.55 ^X H NMR (DMSO d ₅ ) : δ = 2 .3 (3H, ε) ; 2.5 (6H, s); 4.68 (2H, s); 6.43 (2H, s, interchangeable with CFjCOOD) ; 6.91 (2H, S); 7.1 it 7.3 (4H, m) ; 10.5 (1H, p ' replace the first one too with CF3 COOD).

The starting material, (2-methylphenyl)methanesulfonic acid, is prepared from α-chloro-ortho-xylene by the method described by J. Nakayama et al. (Tetrahedron Letters, 25 (40), p. 4553, 1984).

The yield is 31% of theory.

The melting point is 46 to 48 °C.

1H NMR (CDCl 3 ): δ = 2.4 (3H, s); 4.9 (2H, s); 7.15-7.40 (4H,m)

Example 52 (Method A2)

4-Bromo-N-[3,5-dimethyl-4-[(nitromethyl)sulfonyljphenyl] — (2 — t 4 4 4 •44 4·4 ···· *4* « fluorophenyl)methanesulfonamide

4-Bromo-N- [3-[[3,5-dimethyl-4-[ (nitromethy 1 ) su 1 phone 1 ] pheny 1 ]-( 2-f 1 uor pheny 1 ) me t hansu 1 The fonamide is obtained by the method according to Example 2, using as starting material 3 g (12.28 mmol) of 3,5-dimethyl-4-((nitromethyl)sulfonyl)aniline, 57 ml of anhydrous tetrahydrofuran, 2 ml (24 .7 mmol) of pyridine and 5.3 g (19.78 mmol) of (4-bromo-2-fluorophenyl)methanesulfonyl chloride. After evaporation of the solvent, the residue is chromatographed twice on silica using methylene chloride as an eluent and recrystallized with twice from the hexane/ethyl acetate system.

The yield is 1.1 g (18% of theory).

The melting point is 152 to 154 °C (hexane/ethyl acetate). Elementary analysis: C ₁₆ H ₁₆ BrFN ₂ 0sS ₂ (M = 495.35) C%H% Br% F% N% WITH% calculated 38.80 3.26 16,13 3.84 5.66 12.95 found 38.64 3.22 16,15 3.30 5.50 12.86 ¹ H NMR (DMSO d ₆ ): δ = 2.65 (6H, with) 4 .85 (2H, with); 6.60 (2H, s, interchangeable with CF ₃ C00D) ; 7 .08 (2H, with); 7.45- 7.74 (3H, m); 10.8 (IH, s, substitute new with CFaCOOD)

The starting material, (4-bromo-2-fluorophenyl)methanesulfonyl chloride, is prepared from 4-bromo-2-fluorobenzyl bromide by the method described by J. Nakayama et al. (Tetrahedron Letters, 25 (40), p. 4553, 1984).

The yield is 90% of theory.

The oil is purified by flash chromatography on silica using methylene chloride as an eluent.

*H NMR (CDCl 2 ): δ = 4.8 (2H, s); 7.2-7.4 (4H, m)

Example 53 (Method A2) • 0 0» » · · · » · 0 0 •00 *00 * · ·· *0 • 00* ·00 <

N-[3,5-Dimethyl-4-[(nitrimethyl)sulfonyl]phenyl]-cyclohexyl meth hansu 1 fonamide

3.2 g (16.1 mmol) of cyclohexylmethane 1 fone 1 ch 1 or i du (prepared by the method described by J.F. King et al., J. Am. Chem. Soc. 114(5), p . 1743, 1992) into a mixture cooled to -20 °C, maintained in a vacuum and containing 2 g (8.18 mmol) of 3,5-dimethyl-4-[(nitromethyl)'su 1 fon 1]ani 1 i well, 50 ml of anhydrous tetrahydrofuran and 1.3 ml (16.1 mmol) of pyridine and the resulting mixture is stirred for six hours at a temperature of -20 °C. The mixture is left overnight at a temperature of -20 °C, allowed to warm to room temperature and stirred for 24 hours at room temperature followed by refrigeration for 13 hours. The mixture is left in the water. acidified to 1N hydrochloric acid to pH 3, extracted with methylene chloride, washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue is purified by chromatography on silica eluting with methylene chloride and recrystallized from the hexane/ethyl acetate system.

% of theory).

128 C.

Elemental analysis: Cis^^OgSj + 17% C ₆ H ₁₄ (M = 404.51 +

0.17 x 86.18) boil under reflux, cool, pour

The yield is 0.085 g (2.5 The melting point is 126 to

C% H% N% WITH% incl 48.77 6.34 6.68 15.30 found 48 _; 53 6.20 OF 6.66 14.91 ^X H NMR (DMSO d ₆ ): δ = 1.0 tc > 1.3 / (5H, m) ; 1/5 ,·.· (3H, m); 1.75 that 1.90 (3H,' m) ; 2 .5 (6H, with); 3 _Of 15

1.7 interchangeable with CF3COOD} ;

3.22 (2H, m); 6.48 (2H, s,

7 _; 03 (2H, s); 10.5 (IH, s, interchangeable with CF3COOD)

Example 54

Sodium salt N-[3,5-dimethyl-4-Γ(nitromethyl)su1fony 1]pheny1]69 ♦ * ·· • 4 4 • 4 4 · 4 • 4 4 * 4 • ·4 4 ·« ·4

4 4 ·

4 4 4

4*4 >44

4

4« 4 4 of benzenesulfonamide

A mixture of 0.34 g (0.884 mmol) N-[3,5-dimethy 1-4-[ (nitr omelyh 1 } su 1 fony 1 ] pheny 1 ] benzene 1 fonami du and 0.149 g (1.77 mmol) of sodium hydrogen carbonate in 15 ml of distilled water was stirred for 24 hours at room temperature in vacuo and recrystallized from the system methane 1/ether.

The yield is 0.22 g (58% of theory).

Melting point is 253 to 255 °C (methane/ethyl ether).

Elementary analysis ^: Úi5Hii)N2Na20sS2 + 0.65 h ₂ o (M - incl C% H% N% On% WITH% found 40.94 3.50 6.37 10.45 14 _f 57 41.18 3.43 6.46 10.52 ¹⁴ of 25 ¹ H NMR (DMSO d _s ) : δ = 2.44 (6H, s); 6.98 (2H, with) 7.05 <1H, s, e: m) ; 7.8 - 7 z amen i t e1ny s,9 (2H, m) CF3COOD) ; 7.46 - 7.65 (3H,

Example 55

N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]benzenesulfonamide calcium salt

A mixture of 0.34 g (0.88 mmol) of N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]benzenesulfonamide and 0.033 g (0.88 mmol) of calcium hydroxide in 20 ml of deionized water is stirred after for one hour at 25°C and then for 15 minutes at 70°C. The obtained solution is filtered while hot and evaporated in vacuo. The solid residue is recrystallized from the methanol/ether system,

The yield is 0.08 g (22% of theory).

*· • * 9 • · ·»*» ···· *· ·· • · · • · · 4 • · · · • · β • 4 «« «4 * * · 4 »4 4 ··« ·

• 4 99

The melting point is 195 to 197 °C (methane 1/ethyl ether).

Elemental analysis: ' C3oH3oCaN ₄ Oi ₂ S ₄ + 2H ₂ O <M = 8.42.93) C% H% Ca% N% WITH% calculated ^2 75 4.06 4.75 6.65 15,21 found ^2 52 4.17 4.74 6.40 14.81 ^: H NMR (DMSO d ₆ ) : : δ = 2.43 (6H, s); 6.5 (IH, s, interchangeable with CF3COOD) ; 6,7 (2H, s); 7.4 7.6 (3H, m); 7.7 7,. 8 (2H, m); 10 _y 5 (IH, with, interchangeable

with CF3C.OOD) .

Example 56 {Method F1)

N,N'-Bis-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-1,8-octanediamide

0.8637 g (4.09 mmol) of suberoic acid is added to a mixture of 2 g (8.18 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulfonyl]aniline, 50 ml of anhydrous tetrahydrofuran and 1.64 g (16.3 mmol) of calcium carbonate under nitrogen and the resulting mixture is stirred overnight at room temperature. The mixture is poured into water, acidified with dilute hydrochloric acid to pH 3, and the undissolved part is filtered off. The filtrate is extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue is combined with the first undissolved fraction and recrystallized from the ethanol/dimethyl formamide system.

The yield is 0.79 g (15.4% of theory).

The melting point is 235 to 238 *C (ethanol 1/dimethylformamide).

Elemental analysis: C ₂ sH3 ₄ N ₄ OioS2 (M = 626.68)

C% H% N% WITH% calculated 49.83 5.47 8.94 10.23 to climb 49.96 5.60 9.16 9/86 IR: v = 3363 a 1667 cm' ^{1 X} H NMR (DMSO d ₆ ) : δ = 1.25 -T 1.35 (4H, m); 1.5 -

« · ftftftft • ft ftft »

• ftftft e· «· • · *·*« • · • ft ftft • ft ftft ft *· • ·· ft ft·· ft • ft • ft •

ft ftftft •

ft· (4H, m) ; 2.3 (4H, t); 2.48 (12H, s); 6.42 (4H, s, interchangeable with CF ₃ COOD); 7.5 (4H, s); 10.2 (2H, s, interchangeable with CF3COOD).

Example 57 (Method F1)

N,N'-Bis-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-1,5-pentand i amide

Add 0.691 g (4.09 mmol) of glutaric acid to a mixture of 2 g (8.18 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulfonyl]aniline, 50 ml of anhydrous tetrahydrofuran and 1 .64 g (16.3 mmol) of calcium carbonate under nitrogen and the resulting mixture was stirred for 24 hours at room temperature. The mixture is poured into water, acidified with dilute hydrochloric acid to pH 3. extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The obtained solid is recrystallized from the hexane/ethyl acetate system.

The yield is 0.49 g (20% of theory).

The melting point is 207 to 210 °C (hexane/ethyl acetate).

Elementary ana 1 yza : c ₂₃ H23N ₄ OiqS2 (M = 584.606)

C% H% N% WITH% you ^c čea/e 47.25 4.83 9.58 10.97 ruA ³ woman 47.06 4.87 9.46 10.65 IR: v = 3300 and: . 1684 cm ^{1 TH} NMR (DMSO d ₅ ) : δ = 1.63 (2H, q) ; 2.18 (4H, t); (12H, s); 6.22 (4H, s, e interchangeable with CF ₃ COOD) ;

(4H, s); 10.04 (2H, s, interchangeable with CFsCOOD).

Example 58 (Method G1)

N,N'-Bis-[3,5-dimethyl-4-[(nitromethyl)sulfonyl J-phenyl]-1,3-benzenedisulfonamide

1.1 g (4.09 mmol) of 1,3-benzenedisulfonyl chloride is added all at once to a mixture of 2 g (8.18 mmol) of 3,5-dimethyl-4-[(nitrometh72 • · •······« 1]aniline, 38 mL of anhydrous tetrahydrofuran, and 1.63 g (16.1 mmol) of calcium carbonate under nitrogen. The resulting mixture was stirred for 24 hours at room temperature and for 40 hours at 50°C. The reaction mixture is cooled to room temperature, poured into water, extracted with methylene chloride, the organic phase is washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue is purified (by silica chromatography (at -30 °C) using first methylene chloride as an eluent and then the system methyl ether/ethyl acetate (3:1) to obtain the desired product, which is recrystallized first from the system hexane/ methylene chloride and then from the system ethylacetate/hexane/methylene chloride id.

The yield is 0.4 g (14% of theory).

The melting point is 191 to 192 °C (ethyl acetate/hexane/methylench 1 Οτι d ).

Elemental analysis: c ₂ 4H26N ₄ Oi2S4 + 0-18 CH ₃ C00Et (M = 706.62)

C% H% N% WITH% calculated 43^3 3.91 7.93 18.15 found 43.33 3.99 7.96 17^75 IR: V = 3245, 1595 and' 1 559 cm ¹ NMR (DMSO d ₆ ): δ = 2, 54 (12 H, s); 6.51 (4H, with, interchangeable with CF ₃ C00D) ; 7.06 (4H, s); 7 _of 9 (1H, t) ; 8.2 (2H, d); 8.48 (1H, with) ; 11.4 (2H, S, replace the first one as well

with CFaCOOD).

Example 59 (Method F1)

N,N'-Bis-[3,5-dimethyl-4-[(nitromthy1)sulfonyl]phenyl]ethane amide

Add 0.35 ml (4.09 mmol) of oxalyl chloride to a mixture of 2 g (8.18 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulfonyl]ani 1 i nu, 50 ·····« ·· · * 9· ml of anhydrous tetrahydrofuran and 1.63 g (16.2 mmol) of calcium carbonate under nitrogen, and the resulting mixture was stirred for three days at room temperature and poured into water. The precipitate obtained is filtered off, washed with water, and dried under vacuum. The obtained solid is recrystallized from the system ethanol/dimethylformamide.

The yield is 1.62 g (73% of theory).

(M.p. 246 to 248 C (ethane 1/dimethylformamide). 'Elemental analysis: C ₂₀ H ₂₂ N ₄ Oi ₀ S ₂ (M = 542j 528)

C% H% N% WITH% calculated 44.27 4.09 10.33 11.82 for 1 e woman 44.35 4.23 10.34 11.62

IR: V = 3340 a - 1700 cm' ^{1 X} K NMR (DMSO d ₆ ): δ = 2.58 (12H, s); 6.56 (4H, s, interchangeable with CF ₃ COOD) ; 7 _y 84 (4H, s); 11.2 (2H, s, interchangeable with CF3COOD).

Example 60 {Method F1)

N,N'-Bis-4-[(nitromethyl)sulfonyl]phenyl]-1,5-pentaneamide

0.78 g (4.63 mmol) of glutaric dihydrochloride is added to a mixture of 2 g (9.25 mmol) of 4-[(nitromethyl)sulfone 1]ani 1 i nu (prepared by the method described in US Pat. No. 5,153,227) , 50 ml of anhydrous tetrahydrofuran and 1.85 g (18.5 mmol) of calcium carbonate under nitrogen. The resulting mixture was stirred for four days at room temperature and then heated to 40°C for 24 hours and 60°C for 16 hours. The reaction mixture was cooled, poured into a mixture of water and ice and stirred for four hours at 0 °C. The precipitate obtained is filtered off, washed with water and dissolved in ethyl acetate. The organic phase is washed with water, dried over sodium sulfate, filtered. The solid obtained is recrystallized. The yield is 0.88 g (37% of theory).

and evaporated in vacuo to 1u.

calculated L eno found

up to 205 ° C (ethanol). Ci ₉ H ₂ oN ₄ OioS 2 (M = 528.52) C% H% N% WITH% 43.18 3.81 10.60 12,13 43, 20 3.94 10.42 11/92

NMR (DMSO d ₆ )

6.6 (4H, s,

10.56 (2H, s, interchangeable with CFsCOOD).

δ - 1.9 - 2.1 (2H, m); 2.55 (4H, t);

interchangeable _with CF ₃ COOD) ; 7.95 (8H, s);

Example 61 (Method Fl)

N,N'-Bis-[3,5-dimeth. hy 1 -4 - [ (nitromet hy 1 ) sulfone 1 Jphenyl ] - 1 ,4butanediamide

0.64 g (4.14 mmol) of succinyl chloride is added to a mixture of 2 g (8.18 mmol) of 3,5-dimethyl-4-[(π nitromethyl)sulfonyl]aniline, 50 ml of anhydrous tetrahydrofuran and 1.6 g (16.3 mmol) of calcium carbonate under nitrogen and the resulting mixture was stirred for six days at room temperature. The mixture is poured into a mixture of water and ice, acidified with 1N hydrochloric acid to pH 3, and the resulting precipitate is filtered off, washed with water and dried under vacuum. The solid product obtained is washed with hot ethyl acetate and recrystallized from ethanol.

The yield is 0.115 g (4.8% of theory).

The melting point is 226 to 228 *C (ethanol).

Elemental analysis:

(M = 580.199) calculated found

C22H26N4O10S2 + 0 _; 06 EtOH + 0.5 C% H% N% WITH% 45.63 4.74 9.62 11.01 46.03 4.63 9.63 10.53

·«»» ·»· · * · • e » » · · · · * * · • » »9 · · * » *··*·· • * · · · · · · ···» *«· · ·* ·* ·» ♦» ^X H NMR (DMSO d ₆ ): δ = 2.5 (6H, s); 2.7 (4H, s); 6 ₅ 44 ( ^4H 's, interchangeable with CF ₃ COOD) ; 7.5 (4H, s); 10.4 (2H, s, interchangeable with CF3COOD)..

Example 62 (Method F1)

N,N'-Bis-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-1,3propane and amide

0.58 g (4.14 mmol) of ammonium dichloride is added to a mixture of 2 g (8.18 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulfonyl]aniline, 50 ml of anhydrous tetrahydrofuran and 1.6 g (16.3 mmol) of calcium carbonate under nitrogen and the resulting mixture was stirred for 24 hours at room temperature. The mixture was poured into a mixture of water and ice, acidified with 1N hydrochloric acid to pI 3, extracted with ethyl acetate, washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The solid product obtained is recrystallized from the hexane/ethyl acetate system. The yield is 0.2 g (9.8% of theory).

Melting point is 197-199°C (hexane/ethyl acetate).

Elemental analysis: Cu^NaOioSi + 0.5 H ₂ 0 + 0.1 EtOAc (M = 574.396)

calculated C% H% N% WITH% to climb 44.75 4.53 9.75 11,17 44.88 4.56 9.62 10/78 NMR (DMSO d ₆ ): δ = 2.6 (12H, s); 3.65 (2H, s); 6.55 (4H, with, interchangeable with CF3COOD) ; 7.6 (4H, s); 10, 6

(2H, s, interchangeable with CFaCOOD).

Example 63 (Method H)

N,N'-Bis-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]pheny 1] urine and on • · · · I» * ·

Add 0.5 ml (4.09 mmol) of trichomethyl chloroformate dropwise to a mixture of 2 g (8.18 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulfonyl]aniline, 60 ml of anhydrous tetrahydrofuran and 0.54 g (5.39 mmol) of calcium carbonate under nitrogen. The resulting mixture was stirred for 24 hours at room temperature, refluxed for eight hours and left for 4 days at room temperature. The mixture is poured into water and the precipitate obtained is filtered off, dried and recrystallized from ethanol.

The yield is 0.48 g (20% of theory).

The melting point is 224 to 226 °C (ethanol).

Elemental analysis: C19H22N4Q9S2 + 0.3 EtOH + 0.3 H ₂ 0 (M = 533.765)

calculate eno C% H% N% WITH% for 1 ezeno 44.11 4.61 10.50 12.02 44.43 4 _of 43 10.75 11.76

^Χ Η NMR (DMSO d ₆ ): δ = 2.53 (12H, s); 6.49 (4H, s, interchangeable with CF 3 COOD); 7.4 (4H, s); 9.33 (2H, s, interchangeable with CF3COOD).

Example 64 (Method G2)

N,N'-Bis-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-1,3benzenedimethansulfanamide

2.5 g (8.2 mmol) of 1,3-benzenedimethane 1fone 1dichloride (prepared by the method described by J. Lichtenberger et al., Bull. Soc. Chim. Fr., p. 369, 1961) is added all at once to the mixture 4 g (16.3 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulfone 1]ani 1 i nu, 76 ml of anhydrous tetrahydrofuran and 5.2 ml (64.3 mmol) of pyridine under nitrogen. The resulting mixture is stirred overnight at room temperature. The reaction mixture is poured into 500 ml of water, acidified with 1N hydrochloric acid, extracted with methyl chloride, washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue is purified by chromatography on silica eluting with methylene chloride and recrystallized from methylene chloride/hexane and rechromatographed on silica eluting with ethyl acetate/hexane (1:1).

the yield is 0.35 g (6% of theory).

The melting point is 124 to 130 °C (ethyl acetate/hexane).

Elemental analysis: C ₂ 6H ₃ oN ₄ 0 ₁₂ S ₄ + 0.3 EtOAc + 0.2 H ₂ O (M = 748.847)

calculated C% H% N% WITH% found 43.63 4.41 7.48 17.13 43.96 4.44 7.27 17.05 ^X H NMR (DMSO d ₆ ); δ = 2.5 (12H, s); IN (4H, s); 6.48

(4H, interchangeable with CF ₃ C00D) ; 6.95 (4H, s); 7.2

7.4 (4H, m); 10.5 (2H, s, interchangeable with CF3COOD).

Technical usability

A derivative of nitromethylthiobenzene as an aldose reductase inhibitor for the production of pharmaceutical preparations, especially for the treatment of diabetic complications such as cataracts, retinopathy, neuropathy, nephropathy and such as certain vascular diseases

Claims (22)

PATENTOVÉ Compound of Formula I P-NH? ? S (O) n -C-N X W // ’', X - where P is i) i is i - (CO-NH) _m -SO 2 -R, or group iii) S (O) n - C - N X O o wherein R is phenyl. benzyl, diphenylmethyl, naphthyl, cycloalkyl and C1-C4 alkyl having 3 to 7 carbon atoms in the cycloalkyl moiety and a styryl group optionally substituted by one or more Z groups which are the same or different, or represents an aromatic heterocyclic group having from 3 to 5 carbon atoms with one or two heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, optionally substituted by one or more Z groups which are the same or different and optionally conjugated to one or two phenyl rings which are optionally substituted with one or more Z groups which are the same or different, or R is C 1 -C 4 alkyl optionally substituted by one or more halogen atoms which may be the same or different, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkyl and C 1 -C 7 alkyl; up to 4 carbon atoms in the alkyl moiety, Z is halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, and C 2 -C 5 alkylamino, C 1 -C 4 alkylsulfonyl, and 1-C 1 -C 4 -hio and phenyl, X is hydrogen or halogen, m 0 or 1, η 0, 1 or 2, T 1 and T 2 are independently hydrogen or C 1 -C 4 alkyl, at 0 or 1 A is an alkylene group having 1 to 8 carbon atoms or a group of the formula wherein y is an integer of 0, 1, 2, 3 and 4, and when P is ii), A may also be a bond, and tautomeric forms and addition salts thereof pharmaceutically acceptable bases. • · * · A compound of formula I according to claim 1, wherein P is - (CO-NH) m-SO 2 -R. R is phenyl, diphenylmethyl, naphthyl and styryl, optionally substituted by one or more Z, which are the same or different, or R is an aromatic heterocyclic group having from 3 to 5 carbon atoms with one or two heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, optionally substituted by one or more Z groups, which are the same or different and optionally conjugated to one or two phenyl rings which are optionally substituted by one or more Z groups which are the same or different, or R is C 1 -C 4 alkyl optionally substituted by one or more halogen atoms which may be the same or different, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkyl and C 1 -C 7 alkyl; up to 4 carbon atoms in the alkyl moiety, Z, X, m and n are as defined in claim 1, and tautomeric forms and addition salts thereof with pharmaceutically acceptable bases. A compound of formula I according to claim 1, wherein P is - (CO-NH) m-SO 2 -R, wherein R is phenyl; a phenyl group substituted with one or more Z groups which are the same or different: a benzyl group; a benzyl group substituted with one or more Z groups which are the same or different; C 1 -C 4 alkyl optionally substituted by one or more halogen atoms which are the same or different; (C 3 -C 7) cycloalkyl; C 3 -C 7 cycloalkyl and C 3 -C 7 alkyl C 1 -C 4 -alkyl and C 1 -C 4 -alkyl; a styryl group; thienyl; pyridyl; naphthyl; dibenzofuryl; or diphenylmethyl; Z is halogen, C1-C4alkyl, C1-C4alkoxy, nitro, trifluoromethyl, trifluoromethoxy, and C2-C5alkylamino, and C1-C4alkylamino; a phenylovoxi group, and X.man are as defined in claim 1, and tautomeric forms and addition salts thereof with a pharmaceutically acceptable base. A compound of formula I according to claims 1 to 3, wherein is P - (CO-NH) m-SOa-R. where it means R is phenyl; a phenyl group substituted with one or more Z groups which are the same or different; a benzyl group; a benzyl group substituted with one or more Z groups which are the same or different; methyl; C 3 -C 7 cycloalkyl; (C 3 -C 7) cycloalkylalkyl and (C 1 -C 4) alkyl: styryl; thienyl; pyridyl; naftylovvou; dibenzofuryl; diphenylmethyl or 2,2,2-trifluoroethyl; Z is fluorine, chlorine, bromine, methyl, methoxy, nitro, trifluoromethyl, trifluoromethoxy, acetamido, methylsulfonyl and phenyl, X is hydrogen or chlorine, m and n are as defined in claim 1, and tautomeric forms and addition salts thereof with pharmaceutically acceptable bases. A compound of the formula I as claimed in claims 1, 3 and 4, wherein the three are the three. P group - (CO-NH) _m -SO 2 -R, where is R is phenyl; a substituted phenyl group by one or more Z groups which are the same or different; methyl; C 3 -C 7 cycloalkyl or C 3 -C 7 alkyl and C 1 -C 4 alkyl and C 1 -C 4 alkyl; a styryl group; thienyl; pyridyl; naftylovvou; dibenzofuryl; diphenylmethyl or 2,2,2-trifluoroethyl, Z is fluorine, chlorine, bromine, methyl, methoxy, nitro, trifluoromethyl, trifluoromethoxy, acetamido, methylsulfonyl and phenyl, X is hydrogen or chlorine, m and n are as defined above, and their tautomeric forms and addition salts with pharmaceutically acceptable bases, A compound of formula I according to claims 1, 3 and 4 selected from the group consisting of N- [3,5-dimethyl-4 - [(nitromethyl) sulfonyl] phenyl] benzenesulfonamide i. 3,4-difluoro-N- [3,5-dimethyl-4 - [(nitromethyl) sulfonyl] phenyl] benzenesulfonamide, 3-bromo-N- [3,5-dimethyl-4 - [(nitromethyl) sulfonyl] phenyl] benzenesulfonamide, N- [3,5-dimethyl-4 - [(nitromethyl) sulfonyl] phenyl] -2- (trifluoromethyl) benzenesulfonamide, N- [3,5-dimethyl-4 - [(nitromethyl) sulfonyl] phenyl] -4-fluorobenzenesulfonamide, N- [3,5-dimethyl-4 - [(nitromethyl) sulfonyl] phenyl] -3-fluorobenzenesulfonamide, N- [3,5-Dimethyl-4 - [(nitromethyl) sulfonyl] phenyl] phenylmethanesulfonamide, 2,3-Difluoro-N- [3,5-dimethyl-4 - [(trifluoromethyl) sulfonyl] phenyl] - MM · benzenesulfonamide, 3,5-difluoro-N- [3,5-dimethyl-4 - [(nitromethyl) sulfonyl] phenyl] benzenesulfonamide, N- [3,5-Dimethyl-4 - [(trimethyl) sulfonyl] phenyl] -2-fluorobenzenesulfonamide. A compound of formula I according to claim 1, wherein β or P is a group of formula T where it means A bond or C 1 -C 8 alkylene group, µ, n, X, Ti and Ta are as defined in claim 1, and tautomeric forms and addition salts thereof with pharmaceutically acceptable bases. A compound of formula I according to claim 1 wherein P is a group of formula -SO ₂ -A-SO ₂ -NH S (O) n CN where is A, n, X, y, T 1 and T 2 are as defined in claim 1 and their tautomeric forms and addition salts with pharmaceutically acceptable bases. • «« V · * ···· 9 Φ • · · A compound of formula I according to claim 1 selected from the group consisting of N, N'-bis [3,5-dimethyl-4 - [(nitromethyl) sulfonyl] phenyl] -1,5-pentadiene, N, N &apos; -bis [3,5-dimethyl- [4 - [(nitromethyl) sulfonyl] phenyl] -1,8 &apos; N, N''bis [4 - [(nitromethyl) sulfonyl] phenyl] -1,5-pentanediamide, N, N'-bis [3,5-dimethyl-4 - [(nitromethyl) sulfonyl] phenyl] ethane i ami d, N, N'-bis [3,5-dimethyl-4 - [(nitromethyl) sulfonyl] phenyl] urea sulfonylphenyl] -1,4-butylamide, N, N '-bis [3,5-dimethy1-4 - [(nitromethyl) sulfonyl] phenyl] -1,3-propanediamine, N, N'-bis [3,5-dimethyl-4 - [(nitromethyl) sulfonyl] phenyl] -1,3-benzenedisulfonamide, N, N &apos; -bis [3,5-dimethylethyl-4 - [(n-trimethylsulfonyl) sulfonyl] -1,3-benzenedimethanesulfones d. A process for the preparation of a compound of formula I according to claims 1 to 6, wherein P is - (CO-NH) m-SO 3 -R 1, X is hydrogen, mO 2, characterized in that a compound of formula II wherein Ti and T 2 are as defined in claim 1, with a sulfonyl chloride of the formula RSO 2 Cl, wherein R is as defined above, in the presence of a base. A process for the preparation of a compound of the formula I as claimed in any one of claims 1 to 5, wherein P is - (CO-NH) _m -SO 2 -R, X is h 9 9 9 9 9 9999 9 99 · 99 99 999 999 9 - S5 «999 9 9 99 1, preferably chlorine, which is allowed to react 2, denoting a compound of the general formula SO 3 -CH 3 -NO 3 (III) wherein R, Ti and Ti are as defined in claim 1, with a suitable Nhalogensuccinimide in the presence of a free radical generator such as 2,2'-azobisisobutyronitrile 1. A process for the preparation of a compound of formula I according to claims 1 to 5, wherein P is - (CO-NH) m-SO 2 -R. X is hydrogen, mlan 2, characterized by. The compound of formula (II) is reacted. wherein T 1 and T 2 are as defined in claim 1, with a sulfonyl isocyanate of the general formula R-SO 2 -NCO, wherein R is as defined in claim 1. A process for the preparation of a compound of formula I according to claims 1 to 5, wherein P is - (CO-NH) m-SO 2 -R. X is hydrogen, man and O, characterized by. by reacting a compound of formula X 'S-CH ₂ -NO ₂ (X) • * 4 9 44 9 4 4 4 9 4 9944 9994 wherein T 1 and T 2 are as defined in claim 1, with a sulfonyl chloride of the formula RSO 2 Cl, wherein R is as defined in claim 1, in the presence of a base. 14. A process for the preparation of a compound of the formula I according to year 1 to 5, wherein P is - (CO-NH) m-SO2 -R. X is, sulphide, mOanl, characterized in that, reacting a compound of formula IV with _NAVOS-CH2 -no ₂ (IV) wherein R, Tt and T: are as defined in claim 1, with an oxidizing agent such as m-chloroperoxybenzoic acid. 15. A process for the preparation of 3,5-dimethyl-4 - [(isomethyl) sulfonyljaniline by basic hydrolysis of N- [3,5-dimethyl-4 - [(nitromethyl) thio] phenyl] acetamide, characterized in that N- is obtained [3,5-Dimethyl-4 - [(nitromethyl) thiophenyl] acetamide by reaction of the nitromethane hydrogen of the formula NaCHaNO: with 4-acetamido-2,6-dimethylphenylthiocyanate. 16. A process for the preparation of a compound of the formula I of the years 1, 7 and 9. wherein P represents a group of the formula II1 according to na-CO- (A-CO) u-NH at 1, X is hydrogen and n2, to react a compound of formula SOs-CIVNOj »« »4 4 445 * * ·· Wherein A and u are as defined in claim 1, in the presence of a base at a molar ratio of a compound of formula II to a compound of formula V of at least 2. P is a group of formula 111) A process for the preparation of a compound of formula I according to claims 1, 8 and 9, wherein it is -SO ₂ -A-SO ₂ -NH '/ = <' f P \ // S (O) n - -CN * In X X is a hydrogen atom and n2 is reacted with a compound of formula (II) therefor. wherein T 1 and T 2 are as defined in claim 1, with a dichloride of formula VI C1-SO ₂ -A-SO ₂ -C 1 in the presence of a base at a molar ratio of compound II to the compound of formula VI at least a second A process for the preparation of a compound of formula I according to claims 1 and 7, wherein P is a group of formula (ii) -CO- (A-CO)-NH C-N i o ~ S8 wherein X is a hydrogen atom, n2 and u are characterized by reacting a compound of formula II wherein T1 and T2 are as defined in claim 1, with trichloromethyl; In the presence of a base, the molar ratio of the compound of formula (II) to the trichloromethyl chloroformate is at least 2. 19. A pharmaceutical composition comprising as active ingredient at least one compound according to any one of claims 1 to 9 together with at least one pharmaceutically acceptable carrier. A pharmaceutical composition according to claim 18, characterized by sowing. The composition is in the form of immediate release tablets. for controlled release gelatin capsules, injectable solutions, creams or eye drops. Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament product for the inhibition of aldosecretase. Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment of diabetic complications such as cataracts, retinopathy, neuropathy, nephropathy and certain vascular diseases.